WO2023028519A2 - Methods of treating substance use disorder - Google Patents
Methods of treating substance use disorder Download PDFInfo
- Publication number
- WO2023028519A2 WO2023028519A2 PCT/US2022/075393 US2022075393W WO2023028519A2 WO 2023028519 A2 WO2023028519 A2 WO 2023028519A2 US 2022075393 W US2022075393 W US 2022075393W WO 2023028519 A2 WO2023028519 A2 WO 2023028519A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- patient
- use disorder
- treating
- compound
- pharmaceutically acceptable
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 484
- 208000011117 substance-related disease Diseases 0.000 title abstract description 208
- 150000001875 compounds Chemical class 0.000 claims abstract description 453
- 150000003839 salts Chemical class 0.000 claims abstract description 384
- 208000004756 Respiratory Insufficiency Diseases 0.000 claims abstract description 59
- 206010038678 Respiratory depression Diseases 0.000 claims abstract description 59
- 208000026251 Opioid-Related disease Diseases 0.000 claims description 246
- 208000007848 Alcoholism Diseases 0.000 claims description 242
- 208000025746 alcohol use disease Diseases 0.000 claims description 239
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 claims description 211
- 239000008280 blood Substances 0.000 claims description 202
- 210000004369 blood Anatomy 0.000 claims description 202
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 193
- 239000001301 oxygen Substances 0.000 claims description 193
- 229910052760 oxygen Inorganic materials 0.000 claims description 193
- 230000036387 respiratory rate Effects 0.000 claims description 171
- 230000000241 respiratory effect Effects 0.000 claims description 163
- 229960005181 morphine Drugs 0.000 claims description 105
- 230000007423 decrease Effects 0.000 claims description 58
- 208000024891 symptom Diseases 0.000 claims description 18
- 229960001736 buprenorphine Drugs 0.000 claims description 17
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 17
- 210000002700 urine Anatomy 0.000 claims description 13
- 229940005483 opioid analgesics Drugs 0.000 claims description 10
- 230000029058 respiratory gaseous exchange Effects 0.000 claims description 6
- 230000001186 cumulative effect Effects 0.000 claims description 5
- 238000005315 distribution function Methods 0.000 claims description 5
- GVGLGOZIDCSQPN-PVHGPHFFSA-N Heroin Chemical compound O([C@H]1[C@H](C=C[C@H]23)OC(C)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4OC(C)=O GVGLGOZIDCSQPN-PVHGPHFFSA-N 0.000 claims description 4
- 229960002428 fentanyl Drugs 0.000 claims description 4
- USSIQXCVUWKGNF-UHFFFAOYSA-N 6-(dimethylamino)-4,4-diphenylheptan-3-one Chemical compound C=1C=CC=CC=1C(CC(C)N(C)C)(C(=O)CC)C1=CC=CC=C1 USSIQXCVUWKGNF-UHFFFAOYSA-N 0.000 claims description 3
- BRUQQQPBMZOVGD-XFKAJCMBSA-N Oxycodone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C BRUQQQPBMZOVGD-XFKAJCMBSA-N 0.000 claims description 3
- 229960001797 methadone Drugs 0.000 claims description 3
- 229960002085 oxycodone Drugs 0.000 claims description 3
- TVYLLZQTGLZFBW-ZBFHGGJFSA-N (R,R)-tramadol Chemical compound COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-ZBFHGGJFSA-N 0.000 claims description 2
- 206010012335 Dependence Diseases 0.000 claims description 2
- XADCESSVHJOZHK-UHFFFAOYSA-N Meperidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 claims description 2
- UQCNKQCJZOAFTQ-ISWURRPUSA-N Oxymorphone Chemical compound O([C@H]1C(CC[C@]23O)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O UQCNKQCJZOAFTQ-ISWURRPUSA-N 0.000 claims description 2
- 229950004689 carfentanil Drugs 0.000 claims description 2
- YDSDEBIZUNNPOB-UHFFFAOYSA-N carfentanil Chemical compound C1CN(CCC=2C=CC=CC=2)CCC1(C(=O)OC)N(C(=O)CC)C1=CC=CC=C1 YDSDEBIZUNNPOB-UHFFFAOYSA-N 0.000 claims description 2
- 229960004193 dextropropoxyphene Drugs 0.000 claims description 2
- XLMALTXPSGQGBX-GCJKJVERSA-N dextropropoxyphene Chemical compound C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 XLMALTXPSGQGBX-GCJKJVERSA-N 0.000 claims description 2
- XYYVYLMBEZUESM-UHFFFAOYSA-N dihydrocodeine Natural products C1C(N(CCC234)C)C2C=CC(=O)C3OC2=C4C1=CC=C2OC XYYVYLMBEZUESM-UHFFFAOYSA-N 0.000 claims description 2
- LLPOLZWFYMWNKH-CMKMFDCUSA-N hydrocodone Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)CC(=O)[C@@H]1OC1=C2C3=CC=C1OC LLPOLZWFYMWNKH-CMKMFDCUSA-N 0.000 claims description 2
- 229960000240 hydrocodone Drugs 0.000 claims description 2
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 claims description 2
- WVLOADHCBXTIJK-YNHQPCIGSA-N hydromorphone Chemical compound O([C@H]1C(CC[C@H]23)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O WVLOADHCBXTIJK-YNHQPCIGSA-N 0.000 claims description 2
- 229960001410 hydromorphone Drugs 0.000 claims description 2
- 229960005118 oxymorphone Drugs 0.000 claims description 2
- 229960000482 pethidine Drugs 0.000 claims description 2
- 229960004380 tramadol Drugs 0.000 claims description 2
- TVYLLZQTGLZFBW-GOEBONIOSA-N tramadol Natural products COC1=CC=CC([C@@]2(O)[C@@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-GOEBONIOSA-N 0.000 claims description 2
- LLPOLZWFYMWNKH-UHFFFAOYSA-N trans-dihydrocodeinone Natural products C1C(N(CCC234)C)C2CCC(=O)C3OC2=C4C1=CC=C2OC LLPOLZWFYMWNKH-UHFFFAOYSA-N 0.000 claims description 2
- RMRJXGBAOAMLHD-IHFGGWKQSA-N buprenorphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)CN2CC1CC1 RMRJXGBAOAMLHD-IHFGGWKQSA-N 0.000 claims 3
- PJMPHNIQZUBGLI-UHFFFAOYSA-N fentanyl Chemical compound C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 PJMPHNIQZUBGLI-UHFFFAOYSA-N 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 184
- 239000003814 drug Substances 0.000 description 112
- 238000011282 treatment Methods 0.000 description 72
- 241001465754 Metazoa Species 0.000 description 65
- 230000000694 effects Effects 0.000 description 47
- 238000004519 manufacturing process Methods 0.000 description 42
- 239000000902 placebo Substances 0.000 description 37
- 229940068196 placebo Drugs 0.000 description 37
- 108020003175 receptors Proteins 0.000 description 33
- 102000005962 receptors Human genes 0.000 description 33
- 238000012360 testing method Methods 0.000 description 29
- 239000003981 vehicle Substances 0.000 description 28
- 238000004458 analytical method Methods 0.000 description 26
- 230000003285 pharmacodynamic effect Effects 0.000 description 26
- 230000036470 plasma concentration Effects 0.000 description 26
- 241000282693 Cercopithecidae Species 0.000 description 22
- 239000008194 pharmaceutical composition Substances 0.000 description 22
- 238000005259 measurement Methods 0.000 description 20
- 229940079593 drug Drugs 0.000 description 19
- 238000011156 evaluation Methods 0.000 description 18
- 201000009032 substance abuse Diseases 0.000 description 18
- RMRJXGBAOAMLHD-CTAPUXPBSA-N buprenorphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)CN2CC1CC1 RMRJXGBAOAMLHD-CTAPUXPBSA-N 0.000 description 15
- 230000004202 respiratory function Effects 0.000 description 15
- 208000035475 disorder Diseases 0.000 description 14
- 230000009467 reduction Effects 0.000 description 13
- 239000000126 substance Substances 0.000 description 13
- 230000001629 suppression Effects 0.000 description 13
- KPYSYYIEGFHWSV-UHFFFAOYSA-N Baclofen Chemical compound OC(=O)CC(CN)C1=CC=C(Cl)C=C1 KPYSYYIEGFHWSV-UHFFFAOYSA-N 0.000 description 12
- 206010013710 Drug interaction Diseases 0.000 description 12
- 229960000794 baclofen Drugs 0.000 description 12
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 12
- 238000001802 infusion Methods 0.000 description 12
- 241000282567 Macaca fascicularis Species 0.000 description 11
- 230000008859 change Effects 0.000 description 11
- 230000002829 reductive effect Effects 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- ZPUCINDJVBIVPJ-LJISPDSOSA-N ***e Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 description 10
- 239000003937 drug carrier Substances 0.000 description 10
- 230000006870 function Effects 0.000 description 10
- 238000011161 development Methods 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 239000000523 sample Substances 0.000 description 9
- SJZRECIVHVDYJC-UHFFFAOYSA-M 4-hydroxybutyrate Chemical compound OCCCC([O-])=O SJZRECIVHVDYJC-UHFFFAOYSA-M 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- 230000001144 postural effect Effects 0.000 description 7
- 230000003389 potentiating effect Effects 0.000 description 7
- 239000011780 sodium chloride Substances 0.000 description 7
- 231100000736 substance abuse Toxicity 0.000 description 7
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 6
- 230000002411 adverse Effects 0.000 description 6
- 210000003169 central nervous system Anatomy 0.000 description 6
- 230000001149 cognitive effect Effects 0.000 description 6
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 6
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 230000003993 interaction Effects 0.000 description 6
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 6
- 208000020016 psychiatric disease Diseases 0.000 description 6
- 238000012216 screening Methods 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 5
- 230000019771 cognition Effects 0.000 description 5
- 230000003247 decreasing effect Effects 0.000 description 5
- 230000006735 deficit Effects 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 230000001965 increasing effect Effects 0.000 description 5
- XELXKCKNPPSFNN-BJWPBXOKSA-N morphine hydrochloride trihydrate Chemical compound O.O.O.Cl.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O XELXKCKNPPSFNN-BJWPBXOKSA-N 0.000 description 5
- 239000002858 neurotransmitter agent Substances 0.000 description 5
- 229940126027 positive allosteric modulator Drugs 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 239000008215 water for injection Substances 0.000 description 5
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 description 4
- 101100285688 Caenorhabditis elegans hrg-7 gene Proteins 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- 241000282560 Macaca mulatta Species 0.000 description 4
- 241000288906 Primates Species 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 239000000556 agonist Substances 0.000 description 4
- 229940049706 benzodiazepine Drugs 0.000 description 4
- 238000010241 blood sampling Methods 0.000 description 4
- 238000011088 calibration curve Methods 0.000 description 4
- 229960003920 ***e Drugs 0.000 description 4
- 238000009826 distribution Methods 0.000 description 4
- 208000002173 dizziness Diseases 0.000 description 4
- 230000000857 drug effect Effects 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 230000003371 gabaergic effect Effects 0.000 description 4
- 229960002715 nicotine Drugs 0.000 description 4
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 4
- JTJMJGYZQZDUJJ-UHFFFAOYSA-N phencyclidine Chemical compound C1CCCCN1C1(C=2C=CC=CC=2)CCCCC1 JTJMJGYZQZDUJJ-UHFFFAOYSA-N 0.000 description 4
- 238000013112 stability test Methods 0.000 description 4
- 238000007920 subcutaneous administration Methods 0.000 description 4
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 3
- 208000028698 Cognitive impairment Diseases 0.000 description 3
- 208000007590 Disorders of Excessive Somnolence Diseases 0.000 description 3
- 208000012902 Nervous system disease Diseases 0.000 description 3
- 229940123257 Opioid receptor antagonist Drugs 0.000 description 3
- 102100033075 Prostacyclin synthase Human genes 0.000 description 3
- 101710179550 Prostacyclin synthase Proteins 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 238000000540 analysis of variance Methods 0.000 description 3
- 229940125717 barbiturate Drugs 0.000 description 3
- 230000006399 behavior Effects 0.000 description 3
- 150000001557 benzodiazepines Chemical class 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 208000010877 cognitive disease Diseases 0.000 description 3
- 238000002648 combination therapy Methods 0.000 description 3
- 238000011284 combination treatment Methods 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 238000009795 derivation Methods 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- 229960002069 diamorphine Drugs 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 229960003638 dopamine Drugs 0.000 description 3
- 206010013663 drug dependence Diseases 0.000 description 3
- 230000008030 elimination Effects 0.000 description 3
- 238000003379 elimination reaction Methods 0.000 description 3
- IVLVTNPOHDFFCJ-UHFFFAOYSA-N fentanyl citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 IVLVTNPOHDFFCJ-UHFFFAOYSA-N 0.000 description 3
- 238000013095 identification testing Methods 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 230000010534 mechanism of action Effects 0.000 description 3
- 229960005195 morphine hydrochloride Drugs 0.000 description 3
- 239000004570 mortar (masonry) Substances 0.000 description 3
- UZHSEJADLWPNLE-GRGSLBFTSA-N naloxone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C UZHSEJADLWPNLE-GRGSLBFTSA-N 0.000 description 3
- 229960004127 naloxone Drugs 0.000 description 3
- 239000003401 opiate antagonist Substances 0.000 description 3
- 230000035515 penetration Effects 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 229940044551 receptor antagonist Drugs 0.000 description 3
- 239000002464 receptor antagonist Substances 0.000 description 3
- 210000002345 respiratory system Anatomy 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 238000009097 single-agent therapy Methods 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 238000013125 spirometry Methods 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 230000000007 visual effect Effects 0.000 description 3
- 206010001597 Alcohol interaction Diseases 0.000 description 2
- 206010010144 Completed suicide Diseases 0.000 description 2
- 206010013654 Drug abuse Diseases 0.000 description 2
- 206010019233 Headaches Diseases 0.000 description 2
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 2
- 241000233805 Phoenix Species 0.000 description 2
- 206010039897 Sedation Diseases 0.000 description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 2
- 206010041349 Somnolence Diseases 0.000 description 2
- 238000000692 Student's t-test Methods 0.000 description 2
- 206010065604 Suicidal behaviour Diseases 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 230000008484 agonism Effects 0.000 description 2
- VWYANPOOORUCFJ-UHFFFAOYSA-N alpha-Fernenol Chemical compound CC1(C)C(O)CCC2(C)C3=CCC4(C)C5CCC(C(C)C)C5(C)CCC4(C)C3CCC21 VWYANPOOORUCFJ-UHFFFAOYSA-N 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 230000003190 augmentative effect Effects 0.000 description 2
- 230000008499 blood brain barrier function Effects 0.000 description 2
- 210000001218 blood-brain barrier Anatomy 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000003557 cannabinoid Substances 0.000 description 2
- 229930003827 cannabinoid Natural products 0.000 description 2
- 229940065144 cannabinoids Drugs 0.000 description 2
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- -1 elixirs Substances 0.000 description 2
- 235000020937 fasting conditions Nutrition 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 231100000869 headache Toxicity 0.000 description 2
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 2
- 229920000669 heparin Polymers 0.000 description 2
- 229960001008 heparin sodium Drugs 0.000 description 2
- 229960003299 ketamine Drugs 0.000 description 2
- 230000013016 learning Effects 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- 238000007449 liver function test Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 238000000520 microinjection Methods 0.000 description 2
- DQCKKXVULJGBQN-XFWGSAIBSA-N naltrexone Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=O)O)CC1)O)CC1CC1 DQCKKXVULJGBQN-XFWGSAIBSA-N 0.000 description 2
- 229960003086 naltrexone Drugs 0.000 description 2
- 229940127240 opiate Drugs 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 229950010883 phencyclidine Drugs 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 230000003014 reinforcing effect Effects 0.000 description 2
- 231100000279 safety data Toxicity 0.000 description 2
- 230000036280 sedation Effects 0.000 description 2
- 238000010206 sensitivity analysis Methods 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 229910052710 silicon Inorganic materials 0.000 description 2
- 239000010703 silicon Substances 0.000 description 2
- 229960003928 sodium oxybate Drugs 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000007619 statistical method Methods 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 230000003936 working memory Effects 0.000 description 2
- UIKROCXWUNQSPJ-VIFPVBQESA-N (-)-cotinine Chemical compound C1CC(=O)N(C)[C@@H]1C1=CC=CN=C1 UIKROCXWUNQSPJ-VIFPVBQESA-N 0.000 description 1
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 1
- TZWSGOPCLUTFBZ-UHFFFAOYSA-N 2-[1-[2-(4-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]piperidin-2-yl]ethanol Chemical compound N12N=C(C=3C=CC(Cl)=CC=3)C=C2N=C(C)C=C1N1CCCCC1CCO TZWSGOPCLUTFBZ-UHFFFAOYSA-N 0.000 description 1
- WBSMZVIMANOCNX-UHFFFAOYSA-N 3-amino-2-(4-chlorophenyl)-2-hydroxy-1-propanesulfonic acid Chemical compound OS(=O)(=O)CC(O)(CN)C1=CC=C(Cl)C=C1 WBSMZVIMANOCNX-UHFFFAOYSA-N 0.000 description 1
- 239000003477 4 aminobutyric acid receptor stimulating agent Substances 0.000 description 1
- 108010016044 ADX71441 Proteins 0.000 description 1
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 description 1
- 108010082126 Alanine transaminase Proteins 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- 206010027654 Allergic conditions Diseases 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 101800001144 Arg-vasopressin Proteins 0.000 description 1
- 108010003415 Aspartate Aminotransferases Proteins 0.000 description 1
- 102000004625 Aspartate Aminotransferases Human genes 0.000 description 1
- 206010003591 Ataxia Diseases 0.000 description 1
- 101100163949 Caenorhabditis elegans asp-3 gene Proteins 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- 108091006146 Channels Proteins 0.000 description 1
- UIKROCXWUNQSPJ-UHFFFAOYSA-N Cotinine Natural products C1CC(=O)N(C)C1C1=CC=CN=C1 UIKROCXWUNQSPJ-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 208000001640 Fibromyalgia Diseases 0.000 description 1
- 102000005915 GABA Receptors Human genes 0.000 description 1
- 108010005551 GABA Receptors Proteins 0.000 description 1
- 108020004206 Gamma-glutamyltransferase Proteins 0.000 description 1
- 102000018997 Growth Hormone Human genes 0.000 description 1
- 108010051696 Growth Hormone Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 240000008790 Musa x paradisiaca Species 0.000 description 1
- 235000018290 Musa x paradisiaca Nutrition 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- 244000061176 Nicotiana tabacum Species 0.000 description 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 1
- 102000003840 Opioid Receptors Human genes 0.000 description 1
- 108090000137 Opioid Receptors Proteins 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 208000032140 Sleepiness Diseases 0.000 description 1
- 206010042458 Suicidal ideation Diseases 0.000 description 1
- 206010042464 Suicide attempt Diseases 0.000 description 1
- 238000008050 Total Bilirubin Reagent Methods 0.000 description 1
- 102100026383 Vasopressin-neurophysin 2-copeptin Human genes 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000001270 agonistic effect Effects 0.000 description 1
- 201000007930 alcohol dependence Diseases 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000036626 alertness Effects 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000003281 allosteric effect Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229940025084 amphetamine Drugs 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 230000003502 anti-nociceptive effect Effects 0.000 description 1
- 230000001663 anti-spastic effect Effects 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- KBZOIRJILGZLEJ-LGYYRGKSSA-N argipressin Chemical compound C([C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@@H](C(N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)=O)N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(N)=O)C1=CC=CC=C1 KBZOIRJILGZLEJ-LGYYRGKSSA-N 0.000 description 1
- 238000013475 authorization Methods 0.000 description 1
- LFYJSSARVMHQJB-QIXNEVBVSA-N bakuchiol Chemical compound CC(C)=CCC[C@@](C)(C=C)\C=C\C1=CC=C(O)C=C1 LFYJSSARVMHQJB-QIXNEVBVSA-N 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 210000000133 brain stem Anatomy 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000001447 compensatory effect Effects 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 229950006073 cotinine Drugs 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 230000003291 dopaminomimetic effect Effects 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000002964 excitative effect Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 210000003191 femoral vein Anatomy 0.000 description 1
- 102000006640 gamma-Glutamyltransferase Human genes 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 229940049906 glutamate Drugs 0.000 description 1
- 239000000122 growth hormone Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000002489 hematologic effect Effects 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 208000008025 hordeolum Diseases 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 231100000567 intoxicating Toxicity 0.000 description 1
- 230000002673 intoxicating effect Effects 0.000 description 1
- 230000035987 intoxication Effects 0.000 description 1
- 231100000566 intoxication Toxicity 0.000 description 1
- 230000001057 ionotropic effect Effects 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 230000009191 jumping Effects 0.000 description 1
- 238000009533 lab test Methods 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 210000001259 mesencephalon Anatomy 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 229960001252 methamphetamine Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000000116 mitigating effect Effects 0.000 description 1
- 238000011201 multiple comparisons test Methods 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- BQDMEJYNGXEHSW-UHFFFAOYSA-N n-[5-[4-[(4-chloro-3-fluorophenyl)methyl]-6-methoxy-3,5-dioxo-1,2,4-triazin-2-yl]-2-fluorophenyl]acetamide Chemical compound O=C1N(CC=2C=C(F)C(Cl)=CC=2)C(=O)C(OC)=NN1C1=CC=C(F)C(NC(C)=O)=C1 BQDMEJYNGXEHSW-UHFFFAOYSA-N 0.000 description 1
- WIEDUMBCZQRGSY-UHFFFAOYSA-N n-[[2,6-difluoro-4-[3-(1h-1,2,4-triazol-5-yl)phenyl]phenyl]methyl]-2,3-dihydro-1h-inden-2-amine Chemical compound C=1C(F)=C(CNC2CC3=CC=CC=C3C2)C(F)=CC=1C(C=1)=CC=CC=1C1=NC=NN1 WIEDUMBCZQRGSY-UHFFFAOYSA-N 0.000 description 1
- HWYHDWGGACRVEH-UHFFFAOYSA-N n-methyl-n-(4-pyrrolidin-1-ylbut-2-ynyl)acetamide Chemical compound CC(=O)N(C)CC#CCN1CCCC1 HWYHDWGGACRVEH-UHFFFAOYSA-N 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 210000001009 nucleus accumben Anatomy 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 229940001470 psychoactive drug Drugs 0.000 description 1
- 239000004089 psychotropic agent Substances 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000002106 pulse oximetry Methods 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 238000005057 refrigeration Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 description 1
- 229960001225 rifampicin Drugs 0.000 description 1
- 239000012487 rinsing solution Substances 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- SEYCKMQSPUVYEF-LURJTMIESA-N sch-50911 Chemical compound CC1(C)CO[C@@H](CC(O)=O)CN1 SEYCKMQSPUVYEF-LURJTMIESA-N 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 230000037322 slow-wave sleep Effects 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 229940053209 suboxone Drugs 0.000 description 1
- 230000000153 supplemental effect Effects 0.000 description 1
- 230000008093 supporting effect Effects 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 238000002562 urinalysis Methods 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/36—Opioid-abuse
Definitions
- GABA Gamma-aminobutyric acid
- GABAA ionotropic type A
- GAB AB metabotropic type B
- baclofen pharmacokinetic limitations of baclofen, including low blood-brain barrier (BBB) penetration and short plasma half-life (t1/2) further hinders its effective use for curtailing drug-seeking behavior across different substances of abuse (Evenseth et al., 2020). Therefore, there remains an urgent clinical need for effective and well- tolerated GAB AB receptor activation with a favorable pharmacokinetic profile. Engagement of GAB AB receptors with an improved pharmacokinetic profile and lower incidence of undesirable side effects may be achieved with positive allosteric modulators (PAMs).
- PAMs positive allosteric modulators
- methods of treating substance use disorder in a patient in need thereof comprising: i. determining a first respiratory status in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the substance use disorder; and iii. determining a second respiratory status in the patient; wherein the second respiratory status is not lower than the first respiratory status.
- kits for treating substance use disorder in a patient in need thereof comprising administering to the patient the compound of formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the substance use disorder and that does not decrease blood oxygen saturation in the patient.
- kits for treating substance use disorder in a patient in need thereof comprising: i. identifying and/or selecting a patient having substance use disorder; and ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the substance use disorder and that does not increase end tidal CO2 in the patient.
- kits for treating substance use disorder in a patient in need thereof comprising administering to the patient the compound of formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the substance use disorder and that does not decrease respiratory rate in the patient.
- the substance use disorder relates a use disorder of any abusable substance.
- the abusable substance is an opioid, alcohol, nicotine, ***e a ***e derivative, or another drug of abuse such as a benzodiazepine, amphetamine, methamphetamine, and an amphetamine derivative, as well as a dissociative drug such as ketamine, phencyclidine (PCP), and others.
- methods of treating opioid use disorder in a patient in need thereof comprising: i. determining a first blood oxygen saturation in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder; and iii. determining a second blood oxygen saturation in the patient; wherein the second blood oxygen saturation is not lower than the first blood oxygen saturation.
- methods of treating opioid use disorder in a patient in need thereof comprising: i. determining a first end tidal CO2 in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder; and iii. determining a second end tidal CO2 in the patient; wherein the second end tidal CO2 is not higher than the first end tidal CO2.
- the substance use disorder is alcohol use disorder.
- kits for treating alcohol use disorder in a patient in need thereof comprising administering to the patient the compound of formula (I): or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder and that does not cause respiratory depression in the patient.
- methods of treating alcohol use disorder in a patient in need thereof comprising: i. identifying and/or selecting a patient having alcohol use disorder; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder; and iii. determining that the administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof, in step ii. does not cause respiratory depression in the patient.
- kits for treating alcohol use disorder in a patient in need thereof comprising administering to the patient the compound of formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder and that does not decrease blood oxygen saturation in the patient.
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof is comprised in a pharmaceutical composition which further comprises a pharmaceutically acceptable carrier.
- the patient is administered a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
- treating refers to alleviating, abating or ameliorating a disorder or condition or symptoms thereof, preventing additional symptoms, ameliorating the underlying causes of symptoms, inhibiting the disorder or condition, e.g., arresting the development of the disorder or condition, relieving the disorder or condition, causing regression of the disorder or condition, relieving a condition caused by the disorder or condition, or stopping the symptoms of the disorder or condition therapeutically.
- treating in reference to a disorder may include a reduction in severity of one or more symptoms associated with a particular disorder.
- the methods comprise determining the Cumulative Distribution Function, or CDF, of, for example, the percentage of samples of urine of the patient that are negative for opioids.
- the CDF provides a way of comparing the overall continuous distribution of percentage of clean urines from a frequency of 0 to a frequency of 100% in an active drug treatment group vs a placebo-treated group.
- “negative for opioids” means that the patient has at least 80% clean urines by frequency.
- a urine sample is “negative for opioids” when the amount of opioids in the sample is less than 20% by frequency.
- the CDF is a statistical function that can be applied to any measurement of frequency of substance abuse including body fluid (i.e., urine or blood sample), self-reporting of substance use, or other measurement (including but not limited to breathalyzer).
- body fluid i.e., urine or blood sample
- self-reporting of substance use or other measurement (including but not limited to breathalyzer).
- patient refers to any subject, particularly a mammalian subject, for whom diagnosis, prognosis, or therapy is desired, for example, a human.
- treatment regimen and “dosing regimen” are used interchangeably to refer to the dose and timing of administration of the compound of formula (I).
- to “decrease blood oxygen saturation” means to decrease blood oxygen saturation by at least 5%, such as at least 10%, such as at least 15%, such as at least 20%. Thus, the blood oxygen saturation does not “decrease” if, following administration of the compound, the blood oxygen saturation value is less than 5% smaller, or not smaller, than prior to administration of the compound.
- to “decrease respiratory rate” means to decrease the respiratory rate by at least 5%, such as at least 10%, such as at least 15%, such as at least 20%, such as at least 30%, such as at least 40%, or such as at least 50%.
- the compound of formula (I) does not “decrease” the respiratory rate if, following administration of the compound, the respiratory rate decreases by less than 5%, or does not decrease, relative to the respiratory rate prior to administration of the compound.
- kits for treating substance use disorder in a patient in need thereof comprising administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the substance use disorder and that does not cause respiratory depression in the patient.
- kits for treating substance use disorder in a patient in need thereof comprising: i. identifying and/or selecting a patient having substance use disorder; and ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the substance use disorder and that does not cause respiratory depression in the patient.
- methods of treating substance use disorder in a patient in need thereof comprising: i. identifying and/or selecting a patient having substance use disorder; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the substance use disorder; and iii. determining that the administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof, in step ii. does not cause respiratory depression in the patient
- the respiratory depression is determined by measuring the difference, prior to and following administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof, in a parameter selected from end tidal CO2, blood oxygen saturation, or respiratory rate.
- kits for treating substance use disorder in a patient in need thereof comprising administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the substance use disorder and that does not decrease blood oxygen saturation in the patient.
- kits for treating substance use disorder in a patient in need thereof comprising: i. identifying and/or selecting a patient having substance use disorder; and ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the substance use disorder and that does not decrease blood oxygen saturation in the patient.
- methods of treating substance use disorder in a patient in need thereof comprising: i. determining a first blood oxygen saturation in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the substance use disorder; and iii. determining a second blood oxygen saturation in the patient; wherein the second blood oxygen saturation is not lower than the first blood oxygen saturation.
- kits for treating substance use disorder in a patient in need thereof comprising: i. identifying and/or selecting a patient having substance use disorder; and ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the substance use disorder and that does not increase end tidal CO2 in the patient.
- kits for treating substance use disorder in a patient in need thereof, wherein the patient is being treated with buprenorphine, naxolone, or a combination thereof comprising administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the substance use disorder and that does not cause respiratory depression in the patient.
- kits for treating substance use disorder in a patient in need thereof comprising administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the substance use disorder and that does not depress respiration in the patient beyond the level of respiratory depression observed with buprenorphine, naxolone, or a combination thereof.
- methods of treating substance use disorder in a patient in need thereof comprising: i. determining a first respiratory status in the patient; ii. treating the patient with buprenorphine, naxolone, or a combination thereof; iii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the substance use disorder; and iv. determining a second respiratory status in the patient; wherein the second respiratory status is not lower than the first respiratory status.
- methods of treating substance use disorder in a patient in need thereof comprising: i. determining a first respiratory rate in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a first amount that is effective in treating the substance use disorder; iii. determining that a second respiratory rate in the patient following the administration is not lower than the first respiratory rate; and iv. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a second amount that is effective in treating the substance use disorder; wherein the first amount and the second amount are the same or different.
- methods of treating substance use disorder in a patient in need thereof comprising: i. determining a first respiratory rate in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a first amount that is effective in treating the substance use disorder; iii. determining that a second respiratory rate in the patient following the administration is lower than the first respiratory rate; and iv. discontinuing administration of the compound to the patient.
- methods of treating substance use disorder in a patient in need thereof comprising: i. determining a first blood oxygen saturation in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a first amount that is effective in treating the substance use disorder; iii. determining that a second blood oxygen saturation in the patient following the administration is lower than the first blood oxygen saturation; and iv. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a second amount that is effective in treating the substance use disorder; wherein the second amount is lower than the first amount.
- methods of treating substance use disorder in a patient in need thereof comprising: i. determining a first blood oxygen saturation in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a first amount that is effective in treating the substance use disorder; iii. determining that a second blood oxygen saturation in the patient following the administration is lower than the first blood oxygen saturation; and iv. discontinuing administration of the compound to the patient.
- methods of treating substance use disorder in a patient in need thereof comprising: i. determining a first end tidal CO2 in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a first amount that is effective in treating the substance use disorder; iii. determining that a second end tidal CO2 in the patient following the administration is lower than the first end tidal CO2; and iv. discontinuing administration of the compound to the patient.
- the substance can be any abusable substance.
- the substance can also be alcohol, nicotine, ***e and ***e derivatives, other drugs of abuse such as benzodiazepines, amphetamines, methamphetamines, and amphetamine derivatives, as well as dissociative drugs such as ketamine, phencyclidine (PCP), and others.
- drugs of abuse such as benzodiazepines, amphetamines, methamphetamines, and amphetamine derivatives
- dissociative drugs such as ketamine, phencyclidine (PCP), and others.
- kits for treating opioid use disorder in a patient in need thereof comprising administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder and that does not cause respiratory depression in the patient.
- the respiratory depression is determined by measuring the difference, prior to and following administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof, in a parameter selected from end tidal CO2, blood oxygen saturation, or respiratory rate.
- methods of treating opioid use disorder in a patient in need thereof comprising: i. identifying and/or selecting a patient having opioid use disorder; ii. determining a first blood oxygen saturation in the patient; iii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder; and iv. determining a second blood oxygen saturation in the patient; wherein the second blood oxygen saturation is not lower than the first blood oxygen saturation.
- methods of treating opioid use disorder in a patient in need thereof comprising: i. determining a first respiratory status in the patient; ii. treating the patient with buprenorphine, naxolone, or a combination thereof; iii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder; and iv. determining a second respiratory status in the patient; wherein the second respiratory status is not lower than the first respiratory status.
- methods of treating opioid use disorder in a patient in need thereof comprising: i. determining a first blood oxygen saturation in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a first amount that is effective in treating the opioid use disorder; iii. determining that a second blood oxygen saturation in the patient following the administration is lower than the first blood oxygen saturation; and iv. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a second amount that is effective in treating the opioid use disorder; wherein the second amount is lower than the first amount.
- methods of treating opioid use disorder in a patient in need thereof comprising: i. determining a first end tidal CO2 in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a first amount that is effective in treating the opioid use disorder; iii. determining that a second end tidal CO2 in the patient following the administration is lower than the first end tidal CO2; and iv. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a second amount that is effective in treating the opioid use disorder; wherein the second amount is lower than the first amount.
- methods of treating opioid use disorder in a patient in need thereof comprising: i. determining a first end tidal CO2 in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a first amount that is effective in treating the opioid use disorder; iii. determining that a second end tidal CO2 in the patient following the administration is lower than the first end tidal CO2; and iv. discontinuing administration of the compound to the patient.
- Treatment of the opioid use disorder can be provided as a monotherapy, i.e., the compound of Formula I (or a pharmaceutically acceptable salt thereof) alone, or it can be provided as a combination therapy, i.e., along with one or more other agents used for treating opioid use disorder such as methadone, sodium oxybate (GHB), baclofen, naltrexone or naloxone, suboxone, and/or with buprenorphine.
- a monotherapy i.e., the compound of Formula I (or a pharmaceutically acceptable salt thereof) alone, or it can be provided as a combination therapy, i.e., along with one or more other agents used for treating opioid use disorder such as methadone, sodium oxybate (GHB), baclofen, naltrexone or naloxone, suboxone, and/or with buprenorphine.
- GLB sodium oxybate
- baclofen naltrexone or naloxone
- Some embodiments of the methods disclosed herein comprise measuring the amount or frequency of opioid taken by the patient over a period of time prior to administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof, and measuring the amount or frequency of opioid taken by the patient over an equal period of time following administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof.
- the amount of opioid or the frequency of opioid use may also be determined by any clinically suitable method such as evaluation of blood or urine samples (positive/negative or quantitative), or by self-reporting by the patient.
- the methods comprise determining the Cumulative Distribution Function (CDF) of the percentage of samples of urine of the patient that are negative for opioids, as defined herein.
- CDF Cumulative Distribution Function
- the methods comprise determining the frequency of opioid use on the basis of self-reporting by the patient.
- methods of treating alcohol use disorder in a patient in need thereof comprising: i. identifying and/or selecting a patient having alcohol use disorder; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder; and iii. determining that the administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof, in step ii. does not cause respiratory depression in the patient
- methods of treating alcohol use disorder in a patient in need thereof comprising: i. identifying and/or selecting a patient having alcohol use disorder; ii. determining a first blood oxygen saturation in the patient; iii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder; and iv. determining a second blood oxygen saturation in the patient; wherein the second blood oxygen saturation is not lower than the first blood oxygen saturation.
- methods of treating alcohol use disorder in a patient in need thereof comprising: i. determining a first end tidal CO2 in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder; and iii. determining a second end tidal CO2 in the patient; wherein the second end tidal CO2 is not higher than the first end tidal CO2.
- methods of treating alcohol use disorder in a patient in need thereof comprising: i. determining a first respiratory rate in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder; and iii. determining a second respiratory rate in the patient; wherein the second respiratory rate is not lower than the first respiratory rate.
- kits for treating alcohol use disorder in a patient in need thereof comprising administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder and that does not depress respiration in the patient beyond the level of respiratory depression observed with buprenorphine, naxolone, or a combination thereof.
- methods of treating alcohol use disorder in a patient in need thereof comprising: i. determining a first respiratory status in the patient; ii. treating the patient with buprenorphine, naxolone, or a combination thereof; iii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder; and iv. determining a second respiratory status in the patient; wherein the second respiratory status is not lower than the first respiratory status.
- methods of treating alcohol use disorder in a patient in need thereof comprising: i. determining a first respiratory rate in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a first amount that is effective in treating the alcohol use disorder; iii. determining that a second respiratory rate in the patient following the administration is lower than the first respiratory rate; and iv. discontinuing administration of the compound to the patient.
- methods of treating alcohol use disorder in a patient in need thereof comprising: i. determining a first blood oxygen saturation in the patient; ii.
- methods of treating alcohol use disorder in a patient in need thereof comprising: i. determining a first blood oxygen saturation in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a first amount that is effective in treating the alcohol use disorder; iii. determining that a second blood oxygen saturation in the patient following the administration is lower than the first blood oxygen saturation; and iv. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a second amount that is effective in treating the alcohol use disorder; wherein the second amount is lower than the first amount.
- methods of treating alcohol use disorder in a patient in need thereof comprising: i. determining a first end tidal CO2 in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a first amount that is effective in treating the alcohol use disorder; iii. determining that a second end tidal CO2 in the patient following the administration is not lower than the first end tidal CO2; and iv. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a second amount that is effective in treating the alcohol use disorder; wherein the first amount and the second amount are the same or different.
- methods of treating alcohol use disorder in a patient in need thereof comprising: i. determining a first end tidal CO2 in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a first amount that is effective in treating the alcohol use disorder; iii. determining that a second end tidal CO2 in the patient following the administration is lower than the first end tidal CO2; and iv. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a second amount that is effective in treating the alcohol use disorder; wherein the second amount is lower than the first amount.
- methods of treating alcohol use disorder in a patient in need thereof comprising: i. determining a first end tidal CO2 in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a first amount that is effective in treating the alcohol use disorder; iii. determining that a second end tidal CO2 in the patient following the administration is lower than the first end tidal CO2; and iv. discontinuing administration of the compound to the patient.
- the methods comprise determining the Cumulative Distribution Function (CDF) of the percentage of breathalyzer samples, or samples of blood of the patient that are negative for alcohols, as defined herein.
- CDF Cumulative Distribution Function
- the methods comprise determining the frequency of alcohol use on the basis of self-reporting by the patient.
- respiratory status can be effectively evaluated via clinical parameters well known to one of ordinary skill in the art, including respiratory rate (which can be observed directly, i.e., visually, or via plethysmography or spirometry), blood oxygen saturation, or end tidal CO2 measurements.
- respiratory rate which can be observed directly, i.e., visually, or via plethysmography or spirometry
- blood oxygen saturation or end tidal CO2 measurements.
- the method comprises administering the compound of Formula I, or a pharmaceutically acceptable salt thereof, to a patient daily.
- the amount administered is titrated from a lower dose to a higher dose over a period of time. In some embodiments, the amount administered is titrated from a higher dose to a lower dose over a period of time.
- the compound of Formula (I) or pharmaceutically acceptable salt thereof is administered in an amount equal to about 6.25 mg to about 50 mg per day , such as about 12.5 mg per day to about 37.5 mg per day, such as about 25 mg per day. In some embodiments, the compound of Formula (I) or pharmaceutically acceptable salt thereof is administered in an amount equal to about 5 mg to about 100 mg per day, such as about 5 mg per day, about 10 mg per day, about 15 mg per day, about 20 mg per day, about 25 mg per day, about 30 mg per day, about 35 mg per day, about 40 mg per day, or about 50 mg per day.
- the amount per day is administered in one daily dose equal to the total amount per day. In some embodiments case the amount per day is administered in two daily doses, each equal to half of the total amount per day. For example, an amount of 25 mg per day of the compound of formula (I), or a pharmaceutically acceptable salt thereof, may be administered in one dose of 25 mg per day, or in two doses each of 12.5 mg per day, or in three doses each of 8.33 mg per day. For example, an amount of 30 mg per day of the compound of formula (I), or a pharmaceutically acceptable salt thereof, may be administered in one dose of 30 mg per day, or in two doses each of 15 mg per day, or in three doses each of 10 mg per day.
- the compound of Formula (I) or pharmaceutically acceptable salt thereof, or the pharmaceutical composition is administered to the patient orally in an amount from about 6.25 mg to about 50 mg per day, such as about 12.5 mg per day to about 37.5 mg per day, such as about 25 mg per day.
- the compound of Formula (I) or pharmaceutically acceptable salt thereof is administered in an amount equal to about 5 mg to about 100 mg per day, such as about 5 mg per day, about 10 mg per day, about 15 mg per day, about 20 mg per day, about 25 mg per day, about 30 mg per day, about 35 mg per day, about 40 mg per day, or about 50 mg per day.
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in a method of treating substance use disorder in a patient in need thereof, the methods comprising administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the substance use disorder and that does not cause respiratory depression in the patient.
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in a method of treating substance use disorder in a patient in need thereof, the methods comprising: i. determining a first respiratory status in the patient; ii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the substance use disorder; and iii. determining a second respiratory status in the patient; wherein the second respiratory status is not lower than the first respiratory status.
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in a method of treating substance use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having or susceptible to substance use disorder; ii. determining a first respiratory status in the patient; iii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the substance use disorder; and iv. determining a second respiratory status in the patient; wherein the second respiratory status is not lower than the first respiratory status.
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in a method of treating substance use disorder in a patient in need thereof, the methods comprising administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the substance use disorder and that does not decrease blood oxygen saturation in the patient.
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in a method of treating substance use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having substance use disorder; and ii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the substance use disorder and that does not decrease blood oxygen saturation in the patient.
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in a method of treating substance use disorder in a patient in need thereof, the methods comprising: i. determining a first blood oxygen saturation in the patient; ii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the substance use disorder; and iii. determining a second blood oxygen saturation in the patient; wherein the second blood oxygen saturation is not lower than the first blood oxygen saturation.
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in a method of treating substance use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having substance use disorder; ii. determining a first blood oxygen saturation in the patient; iii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the substance use disorder; and iv. determining a second blood oxygen saturation in the patient; wherein the second blood oxygen saturation is not lower than the first blood oxygen saturation.
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in a method of treating substance use disorder in a patient in need thereof, the methods comprising administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the substance use disorder and that does not increase end tidal CO2 in the patient.
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in a method of treating substance use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having substance use disorder; and ii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the substance use disorder and that does not increase end tidal CO2 in the patient.
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in a method of treating substance use disorder in a patient in need thereof, the methods comprising: i. determining a first end tidal CO2 in the patient; ii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the substance use disorder; and iii. determining a second end tidal CO2 in the patient; wherein the second end tidal CO2 is not higher than the first end tidal CO2.
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in a method of treating substance use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having substance use disorder; ii. determining a first end tidal CO2 in the patient; iii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the substance use disorder; and iv. determining a second end tidal CO2 in the patient; wherein the second end tidal CO2 is not higher than the first end tidal CO2.
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in a method of treating substance use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having substance use disorder; ii. determining a first respiratory rate in the patient; iii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the substance use disorder; and iv. determining a second respiratory rate in the patient; wherein the second respiratory rate is not lower than the first respiratory rate.
- a compound of Formula (I), or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating substance use disorder in a patient in need thereof, wherein a first end tidal CO2 is determined in the patient prior to administration of the medicament and a second first end tidal CO2 is determined in the patient after administration of the medicament, in an amount that is effective in treating the substance use disorder, wherein the second end tidal CO2 is not higher than the first end tidal CO2.
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating substance use disorder in a patient in need thereof, wherein the patient has been identified and/or selected as having substance use disorder, wherein a first respiratory rate is determined in the patient prior to administration of the medicament and a second respiratory rate is determined in the patient after administration of the medicament, in an amount that is effective in treating the substance use disorder; wherein the second respiratory rate is not lower than the first respiratory rate.
- a method of treatment disclosed herein comprises determining the value for the patient of a clinical score associated with the substance use disorder. In some embodiments, the method comprises determining that the value of the clinical score at a time point following administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof, is different from the value of the clinical score prior to or at the time of administration.
- the severity of the clinical score is determined by one or more criteria defined in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (also known as DSM-5), incorporated herein in its entirety. In some embodiments, the severity of the clinical score is determined in accordance with the patient global impression severity scale (also known as PGIS), incorporated herein in its entirety. In some embodiments, the severity of the clinical score is determined in accordance with the clinician global impression severity scale (also known as CGIS), incorporated herein in its entirety.
- the compound of Formula (I) or pharmaceutically acceptable salt thereof, or the pharmaceutical composition is administered to the patient in an amount from about 6.25 mg to about 50 mg per day. In some embodiments the compound of Formula (I) or pharmaceutically acceptable salt thereof, or the pharmaceutical composition, is administered to the patient orally in an amount from about 6.25 mg to about 50 mg per day.
- the compound of Formula (I) or pharmaceutically acceptable salt thereof, or the pharmaceutical composition is administered to the patient orally in an amount from about 6.25 mg to about 50 mg per day, such as about 12.5 mg per day to about 37.5 mg per day, such as about 25 mg per day. In some embodiments the compound of Formula (I) or pharmaceutically acceptable salt thereof, or the pharmaceutical composition, is administered to the patient orally in an amount from about 6.25 mg to about 50 mg per day, such as about 12.5 mg per day to about 37.5 mg per day, such as about 25 mg per day.
- the compound of Formula (I) or pharmaceutically acceptable salt thereof is administered in an amount equal to about 5 mg to about 100 mg per day, such as about 5 mg per day, about 10 mg per day, about 15 mg per day, about 20 mg per day, about 25 mg per day, about 30 mg per day, about 35 mg per day, about 40 mg per day, or about 50 mg per day.
- the compound of Formula (I) or pharmaceutically acceptable salt thereof is administered orally in an amount equal to about 5 mg to about 100 mg per day, such as about 5 mg per day, about 10 mg per day, about 15 mg per day, about 20 mg per day, about 25 mg per day, about 30 mg per day, about 35 mg per day, about 40 mg per day, or about 50 mg per day.
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in a method of treating opioid use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having opioid use disorder; and ii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the opioid use disorder and that does not cause respiratory depression in the patient.
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in a method of treating opioid use disorder in a patient in need thereof, the methods comprising: i. determining a first respiratory status in the patient; ii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the opioid use disorder; and iii. determining a second respiratory status in the patient; wherein the second respiratory status is not lower than the first respiratory status.
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in a method of treating opioid use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having or susceptible to opioid use disorder; ii. determining a first respiratory status in the patient; iii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the opioid use disorder; and iv. determining a second respiratory status in the patient; wherein the second respiratory status is not lower than the first respiratory status.
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in a method of treating opioid use disorder in a patient in need thereof, the methods comprising administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the opioid use disorder and that does not decrease blood oxygen saturation in the patient.
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in a method of treating opioid use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having opioid use disorder; and ii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the opioid use disorder and that does not decrease blood oxygen saturation in the patient.
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in a method of treating opioid use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having opioid use disorder; ii. determining a first blood oxygen saturation in the patient; iii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the opioid use disorder; and iv. determining a second blood oxygen saturation in the patient; wherein the second blood oxygen saturation is not lower than the first blood oxygen saturation.
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in a method of treating opioid use disorder in a patient in need thereof, the methods comprising administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the opioid use disorder and that does not increase end tidal CO2 in the patient.
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in a method of treating opioid use disorder in a patient in need thereof, the methods comprising: i. determining a first end tidal CO2 in the patient; ii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the opioid use disorder; and iii. determining a second end tidal CO2 in the patient; wherein the second end tidal CO2 is not higher than the first end tidal CO2.
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in a method of treating opioid use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having opioid use disorder; ii. determining a first end tidal CO2 in the patient; iii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the opioid use disorder; and iv. determining a second end tidal CO2 in the patient; wherein the second end tidal CO2 is not higher than the first end tidal CO2.
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in a method of treating opioid use disorder in a patient in need thereof, the methods comprising: i. determining a first respiratory rate in the patient; ii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the opioid use disorder; and iii. determining a second respiratory rate in the patient; wherein the second respiratory rate is not lower than the first respiratory rate.
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in a method of treating opioid use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having opioid use disorder; ii. determining a first respiratory rate in the patient; iii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the opioid use disorder; and iv. determining a second respiratory rate in the patient; wherein the second respiratory rate is not lower than the first respiratory rate.
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating opioid use disorder in a patient in need thereof, wherein the patient has been identified and/or selected as having opioid use disorder, wherein a first respiratory rate is determined in the patient prior to administration of the medicament and a second respiratory rate is determined in the patient after administration of the medicament, in an amount that is effective in treating the opioid use disorder; wherein the second respiratory rate is not lower than the first respiratory rate.
- the effect of treatment with the compound of formula (I), or a pharmaceutically acceptable salt thereof may be determined, for example, by measuring the reduction in the severity of a symptom of the opioid use disorder.
- the method reduces the severity of a symptom of the opioid use disorder by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35% or at least 40%.
- provided herein are methods as disclosed herein, wherein the decrease in respiratory rate following administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof, is reduced by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35% or at least 40% relative to the decrease in respiratory rate prior to administration.
- a compound of Formula (I) or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, for use in treatment of a patient with alcohol use disorder.
- the compound of Formula (I) or pharmaceutically acceptable salt thereof, or the pharmaceutical composition is administered to the patient orally.
- the compound of Formula (I) or pharmaceutically acceptable salt thereof, or the pharmaceutical composition is administered to the patient in an amount from about 6.25 mg to about 50 mg per day.
- the compound of Formula (I) or pharmaceutically acceptable salt thereof, or the pharmaceutical composition is administered to the patient orally in an amount from about 6.25 mg to about 50 mg per day, such as about 12.5 mg per day to about 37.5 mg per day, such as about 25 mg per day. In some embodiments the compound of Formula (I) or pharmaceutically acceptable salt thereof, or the pharmaceutical composition, is administered to the patient orally in an amount from about 6.25 mg to about 50 mg per day, such as about 12.5 mg per day to about 37.5 mg per day, such as about 25 mg per day.
- the compound of Formula (I) or pharmaceutically acceptable salt thereof is administered in an amount equal to about 5 mg to about 100 mg per day, such as about 5 mg per day, about 10 mg per day, about 15 mg per day, about 20 mg per day, about 25 mg per day, about 30 mg per day, about 35 mg per day, about 40 mg per day, or about 50 mg per day.
- the compound of Formula (I) or pharmaceutically acceptable salt thereof is administered orally in an amount equal to about 5 mg to about 100 mg per day, such as about 5 mg per day, about 10 mg per day, about 15 mg per day, about 20 mg per day, about 25 mg per day, about 30 mg per day, about 35 mg per day, about 40 mg per day, or about 50 mg per day.
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in a method of treating alcohol use disorder in a patient in need thereof, the methods comprising administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the alcohol use disorder and that does not cause respiratory depression in the patient.
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in a method of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having alcohol use disorder; and ii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the alcohol use disorder and that does not cause respiratory depression in the patient.
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in a method of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. determining a first respiratory status in the patient; ii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the alcohol use disorder; and iii. determining a second respiratory status in the patient; wherein the second respiratory status is not lower than the first respiratory status.
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in a method of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having or susceptible to alcohol use disorder; ii. determining a first respiratory status in the patient; iii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the alcohol use disorder; and iv. determining a second respiratory status in the patient; wherein the second respiratory status is not lower than the first respiratory status.
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in a method of treating alcohol use disorder in a patient in need thereof, the methods comprising administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the alcohol use disorder and that does not decrease blood oxygen saturation in the patient.
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in a method of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having alcohol use disorder; ii. determining a first blood oxygen saturation in the patient; iii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the alcohol use disorder; and iv. determining a second blood oxygen saturation in the patient; wherein the second blood oxygen saturation is not lower than the first blood oxygen saturation.
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in a method of treating alcohol use disorder in a patient in need thereof, the methods comprising administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the alcohol use disorder and that does not increase end tidal CO2 in the patient.
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in a method of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having alcohol use disorder; and ii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the alcohol use disorder and that does not increase end tidal CO2 in the patient.
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in a method of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. determining a first end tidal CO2 in the patient; ii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the alcohol use disorder; and iii. determining a second end tidal CO2 in the patient; wherein the second end tidal CO2 is not higher than the first end tidal CO2.
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in a method of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having alcohol use disorder; ii. determining a first end tidal CO2 in the patient; iii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the alcohol use disorder; and iv. determining a second end tidal CO2 in the patient; wherein the second end tidal CO2 is not higher than the first end tidal CO2.
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in a method of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. determining a first respiratory rate in the patient; ii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the alcohol use disorder; and iii. determining a second respiratory rate in the patient; wherein the second respiratory rate is not lower than the first respiratory rate.
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in a method of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having alcohol use disorder; ii. determining a first respiratory rate in the patient; iii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the alcohol use disorder; and iv. determining a second respiratory rate in the patient; wherein the second respiratory rate is not lower than the first respiratory rate.
- a compound of Formula (I), or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating alcohol use disorder in a patient in need thereof, wherein a first end tidal CO2 is determined in the patient prior to administration of the medicament and a second first end tidal CO2 is determined in the patient after administration of the medicament, in an amount that is effective in treating the alcohol use disorder, wherein the second end tidal CO2 is not higher than the first end tidal CO2.
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating alcohol use disorder in a patient in need thereof, wherein the patient has been identified and/or selected as having alcohol use disorder, wherein a first respiratory rate is determined in the patient prior to administration of the medicament and a second respiratory rate is determined in the patient after administration of the medicament, in an amount that is effective in treating the alcohol use disorder; wherein the second respiratory rate is not lower than the first respiratory rate.
- a method of treatment disclosed herein comprises determining the value for the patient of a clinical score associated with the alcohol use disorder. In some embodiments, the method comprises determining that the value of the clinical score at a time point following administration of the compound of Formula (I) is different from the value of the clinical score prior to or at the time of administration.
- the severity of the clinical score is determined by one or more criteria defined in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (also known as DSM-5), incorporated herein in its entirety.
- the severity of the clinical score is determined in accordance with the patient global impression severity scale (also known as PGIS), incorporated herein in its entirety.
- the severity of the clinical score is determined in accordance with the clinician global impression severity scale (also known as CGIS), incorporated herein in its entirety.
- the effect of treatment with the compound of formula (I) may be determined, for example, by measuring the reduction in the severity of a symptom of the alcohol use disorder.
- the potential additive effect of the compound of Formula (I) on the morphine-induced pharmacodynamic effects on the respiratory system was investigated based on the coadministration of morphine and the compound of Formula (I) in male cynomolgus monkeys (4-6 years old) under conscious and non-restrained conditions. Respiratory rate, tidal volume and minute volume were evaluated as the respiratory parameters. Oral and subcutaneous administrations were adopted for the compound of Formula (I) and morphine, respectively. Groups of male monkeys each consisted of 2 to 3 individuals were used.
- Cynomolgus monkey (Seven male animals - 4 to 6 years old at receipt and at the first administration)
- the acclimatization period was from the day of animal receipt to the day before the first administration.
- Compound of Formula (I) and its vehicle (0.5% MC suspension) Oral administration.
- Morphine and water for injection Subcutaneous administration.
- the respiratory function of No. 4 was measured for confirmation and the respiratory rate was higher than that of the predose value of the concomitant treatment of 10 mg/kg morphine and 10 mg/kg of the compound of Formula (I). Therefore, the 9th administration was not performed for No. 4. Moreover, since the respiratory rate remained high, it was not used and the evaluation was performed with No. 1 and 2 from the 9th administration.
- the dosing volume was calculated based on body weights measured on the day before administration (for measurement of respiratory function) or the day of administration (for TK blood sampling) and the dosing value was rounded to the nearest minimum scale value of the syringe from the first decimal place.
- the dosing volumes of morphine and water for injection were rounded up to the minimum scale of the syringe from the second decimal place.
- a required amount of the compound of Formula (I) was weighed and was ground with an agate mortar and pestle.
- the suspension was measured up to the target concentration by addition of 0.5%MC and then mixed by inversion.
- the prepared dosing formulations of the test article were stored under refrigeration (Actual range: 4.2°C to 7.1 °C; acceptable range: 1°C to 15°C) and protected from light, and used within 7 days after preparation.
- the prepared solution was transferred to a glass container.
- the Study Design and the Administration Schedule were as shown below:
- Preamplifier module MAX2275, Buxco Electronics, Inc.
- Temperature-humidity probe used for WBP TRD5716, Buxco Electronics, Inc.
- the respiratory parameters were measured with whole body plethysmograph using a respiratory plethysmograph chamber.
- Respiratory function (respiratory rate, tidal volume and minute volume)
- Respiratory Function (respiratory rate, tidal volume and minute volume)
- TK measurement sample Approximately 0.3 to 0.6 mL of blood was collected from the cephalic vein with a syringe containing heparin sodium and immediately cooled on ice and centrifuged (1830 / g, 10 min, 4°C) to obtain plasma of 0.1 to 0.3 mL or more.
- the obtained plasma (TK measurement sample) was stored in an ultra-low temperature freezer (acceptable range: -90 to -65°C) until shipping.
- a label indicating the study number, animal number, substance name, and dose was attached to each container of the TK measurement sample.
- the blood collected from the control group was discarded.
- the tidal volume As for the tidal volume, it was lower in the 3 mg/kg morphine alone group than that in the control group at 4 h (animal No. 1) and at 8 h (animal No. 2) after administration.
- the tidal volume in the 10 mg/kg morphine alone group was lower than that in the control group at 1 to 8 h (animal No. 1), 1, 2 and 8 h (animal No. 2) and 4 h (animal No. 4) after administration.
- the minute volume As for the minute volume, it was lower in the 3 mg/kg morphine alone group than that in the control group at 4 h after administration (animal No. 1).
- the minute volume of 10 mg/kg morphine alone group was lower than that in the control group at 1, 2 and 8 h (animal No.
- the minute volume a lower value at 1, 2, 4 and 24 h after administration in the animal No. 1, a lower value at 2 and 8 h after administration in the animal No. 2, and a lower value at 1, 2, 4 and 8 h after administration in the animal No. 4 were noted compared to the pre-dose values.
- no clear difference in respiratory rate, tidal volume or minute volume in the animal No.1 and 2 was observed compared to that in the 10 mg/kg morphine control group.
- reactions similar to those of the 10 mg/kg morphine alone group were noted up to 4 h after administration, the respiratory rate increased at 8 h after administration while there was a decrease in minute volume.
- Plasma concentrations of ASP8062 were measured by LC-MS/MS with the following calibration curve ranges Study SNBL.-PKMs-190042 was the calibration curve range of (0.12 to 1200 ug/mL and Study SNBL-PKMs-190074 was the calibration curve runge of 0.1 m
- Plasma Concentrations of ASP8062 alter a Single Oral Administration ef ASP8062 to monkeys
- a self-administration method was used to investigate the potential of ASP8062 for suppressing the reinforcing effects of morphine.
- Three rhesus monkeys were pretreated with ASP8062 (0.3, 1 or 3 mg/kg) by oral administration 1 h prior to a 2-h morphine self-administration session (0.03 mg/kg, iv, per injection) under a fixed-ratio 5 schedule.
- the potential worsening of morphine-induced respiratory suppression by ASP8062 after coadministration of morphine (10 mg/kg, sc) and ASP8062 (10 mg/kg, po) was examined in cynomolgus monkeys using a custom-made whole-body plethysmograph. Plasma concentrations of ASP8062 (3 or 10 mg/kg, po) were assessed in cynomolgus monkeys using liquid chromatography -tandem mass spectroscopy (LC-MS/MS).
- ASP8062 dose-dependently decreased the number of morphine self-administrations, with significant differences from the vehicle-treated group observed at 3 mg/kg in all animals tested. Exposure levels at 3 mg/kg observed in monkeys were comparable to the clinical exposure levels which positive pharmacodynamic effects were previously shown. Further, ASP8062 did not potentiate morphine-induced respiratory suppression up to exposure levels higher than the clinically relevant dose.
- Morphine hydrochloride hydrate JP was purchased from Takeda Pharmaceutical Company Limited (Tokyo, Japan).
- ASP8062 was provided by Astellas Pharm Inc. (Tsukuba, Japan).
- Trial 2 On the first day, the animals were allowed to self-administer morphine (0.03 mg/kg/infusion) without limitations on the number of self-administrations/day; the number of administrations was >11 times and not markedly different from the mean number of selfadministrations in the first trial (within approximately 1/2 or 2-fold of the mean). Subsequently, self-administration with saline was trialed on 1 day. Finally, the animals were subjected to selfadministration with saline (0.25 mL/kg/infusion) for 3 days following pretreatment with vehicle, without limitations on the number of self-administrations/day.
- Trial 3-5 On the first day, the animals were allowed to self-administer morphine (0.03 mg/kg/infusion) without limitations on the number of self-administrations/day; the number of administrations was >11 times and not markedly different from the mean number of selfadministrations in the first trial (within approximately 1/2 or 2-fold of the mean). Subsequently, self-administration with saline was trialed on 1 day. Finally, the animals were subjected to selfadministration with morphine (0.03 mg/kg/infusion) for 3 days following pretreatment with ASP8062 (0.3, 1, or 3 mg/kg/ig infusion), without limitations on the number of self- admini strati ons/ day .
- a custom-made whole-body plethysmograph system for measuring respiratory function in unrestrained monkeys was used.
- the system consisted of the following components: 4CH Bias flow box (GM Company Ltd.); Whole body plethysmography (WBP) chamber (LSI Rulece Co.); flow sensor for WBP (TRD5715, Buxco Electronics, Inc.); preamplifier module (MAX2275, Buxco Electronics, Inc.); and temperature-humidity probe for WBP (TRD5716, Buxco Electronics, Inc.).
- FinePointe software (Version 2.3.1.9, Data Sciences International, Inc.) was used for data acquisition.
- Respiratory parameters were measured according to the method described by lizuka et al. (2010) using a respiratory plethysmograph chamber. Prior to dosing, 3 of the 4 animals were housed and acclimatized to the chamber for more than 16 h. The time immediately after oral administration of ASP8062 (10 mg/kg po) and vehicle was defined as 0 min. Evaluation time points were before administration and 1, 2, and 4 h after administration. Mean values measured for 1 min before each of the evaluation time points were defined as the measurement data.
- Plasma concentrations of ASP8062 (3 or 10 mg/kg, po) were measured using liquid chromatography -tandem mass spectroscopy (LC-MS/MS) at a calibration curve range of 0.12 to 1200 ng/mL or 0.1 to 1000 ng/mL at SNBL, Ltd.
- Pharmacokinetic parameters were calculated using the noncompartmental analysis model of Phoenix WinNonlin (Certara, NJ, USA).
- Respiratory function parameters are reported as mean ⁇ standard deviation (SD).
- SD standard deviation
- data from 3 mg/kg ASP8062 group are expressed as mean ⁇ SD.
- data from the 10 mg/kg ASP8062 group comprising 2 cases are expressed as mean only.
- Data were calculated using Microsoft Excel 2010 (Microsoft Corporation Redmond, WA, USA).
- ASP8062 significantly reduced the mean number of morphine self-administrations observed across 3 days. The effect was dose-dependent and observed at all dose levels of ASP8062 in 1 of the 3 animals and at 3 mg/kg in the remaining 2 animals, compared to vehicle control (Fig. 1). No gross behavioral signs were observed in any animal during the self-administration period.
- Plasma concentrations of ASP8062 after single oral administration to cynomolgus monkeys (no morphine infusion) are shown in Figure 5.
- the Cmax and AUC24 values were 202 ng/mL and 1700 ng h/mL at 3 mg/kg, and 404 ng/mL and 4660 ng h/mL at 10 mg/kg, respectively.
- GAB AB receptor PAM ASP8062
- morphine self-administration after intragastric administration to rhesus monkeys.
- the GAB AB receptor is listed as the National Institute on Drug Abuse’s highest priority pharmacological target for the development of novel therapeutics for treating OUD (Rasmussen et al., 2019).
- PAMs can enhance the effects of GABA at GAB AB receptors and have therapeutic effects similar to agonists but with superior side-effect profiles (Filip et al., 2015).
- Nonhuman primates are more phylogenetically related to humans than any other species (Smith, 2020); similarly, their long lives and complex social systems most resemble those of humans.
- the self-administration paradigm is a commonly recognized standard preclinical model for substance abuse.
- the morphine self-administration method using nonhuman primates adopted in the present study is thought to be reflective of substance abuse in humans.
- the positive findings along with support from the aforementioned MoA strongly suggest that ASP8062 has potential clinical efficacy for treating OUD.
- Cmax and AUC24 values at 70 mg were 165 ng/mL and 1570 ng h/mL, respectively. These exposure levels are comparable to the values obtained in nonhuman primates in the present study (Cmax and AUC24 values were 202 ng/mL and 1700 ng h/mL, respectively, at 3 mg/kg), further supporting the drugs’ potential clinical efficacy in OUD.
- Opioid-induced respiratory depression is a well-known side effect, and the possibility of exaggerating this effect with concomitant administration of ASP8062 is an important issue that requires addressing.
- Opioids depress respiration by activating opioid receptors expressed on neurons within the respiratory networks of the brainstem and outside the CNS (Algera et al., 2019).
- An off-target profiling study demonstrated that ASP8062 at 10 pM (40759 ng/mL) had no appreciable affinity for any of 55 receptors, channels, transporters and/or enzymes, including the human p-opioid receptor (Murai et al., 2019). lizuka et al.
- ASP8062 suppressed morphine self-administration in a non-human primate selfadministration model. Efficacious exposure levels in the preclinical model were comparable to those observed in the clinic with which acceptable safety and GABAergic pharmacodynamic effects have been confirmed. ASP8062 showed no preclinical signs of potentiating morphine- induced respiratory suppression at supratherapeutic exposure levels. These results suggest that ASP8062 may reduce opioid use in OUD patients without serious adverse events, and further development of ASP8062 as a potential treatment option for OUD is warranted.
- ASP8062 + alcohol On Day 1 of each period, ASP8062 or placebo was administered as a single 60-mg oral dose under fasting conditions with 240-mL water.
- ASP8062 60 mg in a newly developed ASP8062 30-mg tablet formulation, was chosen based on the results from a previously conducted relative bioavailability study and was expected to provide plasma ASP8062 exposures comparable to exposures in the previous clinical studies.
- the alcohol dose was 0.6-g ethanol/kg for female subjects and 0.7-g ethanol/kg for male subjects.
- the respective doses were selected as a dose of alcohol (equivalent to approximately 4 units for a 70-kg subject) known to cause a reliable, measurable, and consistent decrease in cognition.
- Alcohol or placebo alcohol was administered as a single oral dose within 10 minutes under the existing fasting conditions, after which subjects had to remain awake in a semi -recumbent position and avoid lying on either the left or right side for 2 hours postdose. Only alcohol or placebo alcohol was allowed from at least 10 hours predose through 4 hours postdose. Subjects were discharged from the clinical unit on Day 5 of each period, on the condition that all required assessments had been performed and that there were no medical reasons for a longer stay in the clinical unit. Subjects returned to the clinical unit on Days 7 and 10 for pharmacokinetic blood sampling. The study was completed with an end-of-study visit, which took place between 5-9 days after Day 10 of Period 4 or at early discontinuation from the study.
- Male subjects and their female spouse/partners who were of childbearing potential were required to use contraception throughout the study period and for 90 days after final administration of the investigational product.
- Subjects were excluded from the study if they had: a) any known or suspected hypersensitivity to ASP8062 or alcohol; liver function tests (alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, and total bilirubin) >1.5x upper limit of normal (ULN) on Day -1 of Period 1; b) a clinically significant history of allergic conditions; c) a history or evidence of any clinically significant cardiovascular, gastrointestinal, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, renal and/or other major disease or malignancy, as judged by the investigator; d) an untreated moderate or severe mental illness; e) a relevant history of suicide attempt or suicidal behavior; f) smoked, used tobacco-containing products and nicotine or nicotine-containing products within 6 months prior to screening, or tested positive for cot
- the primary objective was to assess the potential for pharmacokinetic and pharmacodynamic interaction between ASP8062 and alcohol.
- Primary pharmacokinetic endpoints for ASP8062 in plasma were area under the concentration-time curve (AUC) from the time of dosing extrapolated to time infinity (AUCinf) and maximum concentration (Cmax); AUC from the time of dosing to the last measurable concentration (AUCiast) and Cmax were the primary pharmacokinetic endpoints for plasma ethanol.
- Primary pharmacodynamic endpoints were comprised of the Cogstate battery and postural stability test.
- ASP8062 blood samples were collected on Day 1, predose (ASP8062/placebo ASP8062), and at the following postdose (ASP8062/placebo ASP8062) time points: 15 minutes, 30 minutes, 45 minutes, 60 minutes, 75 minutes, 90 minutes, 105 minutes, 2 hours, 2 hours 30 minutes, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 12 hours, 14 hours, 16 hours (Day 1), 24 hours (Day 2), 36 hours (Day 2), 48 hours (Day 3), 72 hours (Day 4), 96 hours (Day 5), 144 hours (Day 7), and 216 hours (Day 10).
- Plasma concentrations of ASP8062 and ethanol were determined using validated liquid chromatography -tandem mass spectrometry and gas chromatography with flame ionization detection methods, respectively.
- Cogstate battery pharmacodynamic assessments were performed twice on Day -1 of Period 1 as practice assessments.
- the postural stability test assessed via the single-leg stance test was performed once on Day -1 of Period 1 as a practice assessment. All pharmacodynamic tests were repeated on Day 1 of each period, predose (ASP8062/placebo ASP8062), and then postdose (ASP8062/placebo ASP8062) at the following time points: 90 minutes, 2 hours 30 minutes, 4 hours, and 6 hours.
- the secondary objective was to evaluate the safety and tolerability of a single dose of ASP8062 with or without alcohol.
- Secondary endpoints included the nature, frequency, and severity of adverse events (AEs), clinical laboratory tests (hematology, biochemistry, and urinalysis), vital signs (blood pressure and pulse), routine 12-lead electrocardiogram (ECG), Columbia-Suicide Severity Rating Scale (C-SSRS), and SpCh.
- Exploratory objectives included evaluation of the general pharmacokinetic and pharmacodynamic parameters of ASP8062 and alcohol.
- Exploratory pharmacokinetic endpoints measured from ASP8062 plasma were time to peak plasma concentration (tmax), half-life in plasma (t>/ 2 ), apparent clearance (CL/F), and apparent volume of distribution during terminal phase after oral administration (Vz/F); tmax was the exploratory endpoint measured from alcohol plasma. Additional exploratory safety and tolerability endpoints were assessed by the Bond- Lader Visual Analogue Scales (VAS), Addiction Research Center Inventory Scale 49-item short form (ARCI-49), alcohol urge questionnaire (AUQ), drug effects questionnaire (DEQ-5), and a daytime somnolence scale.
- VAS Bond- Lader Visual Analogue Scales
- ARCI-49 Addiction Research Center Inventory Scale 49-item short form
- AUQ alcohol urge questionnaire
- DEQ-5 drug effects questionnaire
- the pharmacokinetic analysis set was used for the analysis of all pharmacokinetic data and consisted of all subjects who received at least one dose of study medication for which concentration data were available in order to facilitate derivation of at least one primary pharmacokinetic parameter of ASP8062.
- the pharmacodynamic analysis set was used for the analysis of all pharmacodynamic data and consisted of all subjects who received at least one dose of the test agents (alcohol and ASP8062) for which sufficient pharmacodynamic measurements were collected.
- the safety analysis set was used for all summaries and analyses of the safety data and consisted of all subjects who received at least one dose of alcohol or ASP8062.
- the pre- and postdose plasma concentration values of ASP8062 for one of the subjects during ASP8062 alone treatment was below the lower limit of quantification (LLOQ; 0.5 ng/mL) and thus were excluded from summary statistics. Additionally, following administration of ASP8062 alone, one subject had approximately 10-fold lower plasma concentrations of ASP8062 compared with other subjects and when compared with the subject's own concentrations during combination treatment; reasons for this low concentration of ASP8062 could not be determined. Therefore, an additional sensitivity analysis was conducted to reassess the PKAS by excluding this particular subject from the statistical assessments.
- LLOQ lower limit of quantification
- the PKAS excluding the subject who showed substantially lower plasma concentrations of ASP8062 following administration of ASP8062 alone (but showed similar ASP8062 exposure compared with other subjects following administration of ASP8062 in combination with alcohol), is presented in the main figures and tables; complete analyses including the potential outlier subject are provided in the supplemental figures and tables ( Figures 15-17, Example 3 Table SI).
- Descriptive statistics were used to summarize plasma pharmacokinetic parameters. To assess the effect of alcohol on the pharmacokinetics of ASP8062 and the effect of ASP8062 on the pharmacokinetics of alcohol, plasma exposures were evaluated bidirectionally and an analysis of variance (ANOVA) model with treatment, period, and sequence as fixed effects and subject as a random effect was fitted on natural logarithm -transformed AUCinf and Cmax.
- ANOVA analysis of variance
- Adverse events were coded using MedDRA v22.0.
- the number and percentage of subjects with treatment-emergent AEs (TEAEs, defined as an AE with onset at any time from first dosing until the last scheduled procedure), investigational product-related TEAEs, TEAEs leading to withdrawal of treatment, investigational product-related TEAEs leading to withdrawal of treatment, serious TEAEs, and investigational product-related serious TEAEs were summarized by system organ class (SOC), preferred term, and treatment condition.
- SOC system organ class
- Example 3 The demographic and baseline characteristics across treatment sequences (1-4) are summarized in Example 3 Table 1.
- the age of randomized subjects included in the study ranged from 25 to 55 years, with a median of 40.5 years across all sequences.
- the population consisted mainly of male subjects (70%) and was primarily Black or African American (65%).
- ASP8062 After administration of alcohol, a minimal increase in total exposure of ASP8062 was observed, with an AUCinf geometric least squares (LS) mean ratio (90% CI) of 105.22% (96.00, 115.34). In addition, a mild increase in peak plasma concentrations of ASP8062 was also observed with a Cmax geometric LS mean ratio (90% CI) of 124.91% (107.48, 145.17).
- LS geometric least squares
- Performance data from four assessments of the Cogstate battery were selected for evaluation of the cognitive pharmacodynamic profile of ASP8062 and alcohol.
- Mean Cogstate battery test results and changes from baseline are presented in Figure 16.
- Subjects who received ASP8062 alone showed numerically worse scores on the Identification, One-back, and GMLT tests compared with placebo up to 4 hours postdose (Example 3 Table S3), but did not show consistent or robust changes in performance on these tests when compared with placebo.
- Subjects who received alcohol alone showed worse performance on the Detection and GMLT tests compared with placebo up to 4 hours postdose and on the One-back test at 2.5 hours postdose (Example 3 Table S4).
- GAB AB receptor PAMs represent a potential therapeutic alternative to conventional GAB AB receptor orthosteric agonists for treatment of substance abuse disorders because the PAMs enhance GAB AB receptor signaling by endogenous neurotransmitters without constitutive receptor stimulation.
- the resulting specific enhancement of GAB AB receptor activity may be associated with reduced side effects and mitigation of tolerance upon repeated administration.
- GAB AB receptors play a major role in various CNS functions; therefore, modulation of GABA transmission can have significant effects.
- the development of agonists targeting this receptor subtype has not translated into the degree of clinical success or regulatory approval that was anticipated due to neurologic complications, potential for abuse, and pharmacokinetic limitations. Development of GAB AB receptor PAMs with reduced potential for abuse and tolerance could address this unmet need. Accordingly, the primary objective of this study was to assess the potential for pharmacokinetic and pharmacodynamic interaction between ASP8062 and alcohol under single-dose conditions.
- baclofen alone had minimal abuse liability in nontreatmentseeking heavy social drinkers and was relatively well tolerated and safe when given in combination with intoxicating doses of alcohol.
- one subject was considered a potential outlier due to substantially lower plasma exposure of ASP8062 when treated with ASP8062 alone.
- the total exposure of ASP8062 and peak plasma concentrations of ASP8062 were reduced when excluding the outlier, the difference in the geometric LS mean ratios was similar between the complete case set and the sensitivity analysis for the PKAS excluding the outlier.
- this subject also appeared to be an outlier in the overall subject population of this study and across the entirety of the ASP8062 phase 1 clinical experience.
- ASP8062 Subjects who received ASP8062 alone did not experience any consistent or robust changes in cognition measurements when compared with those who received placebo. As expected, administration of alcohol alone led to impairment in psychomotor function and executive function assessments. Furthermore, administration of ASP8062 in combination with alcohol worsened performance on the cognitive test when compared with subjects who received alcohol alone. This suggests that there may be a numerically additive interaction between ASP8062 and alcohol. However, ASP8062 alone did not show any consistent or robust negative cognitive effects. Likewise, a consistent potentiation of the effect was not observed.
- the effect of alcohol on cognitive measures is known to occur via a complex interplay between excitatory and inhibitory neurotransmitters, including dopamine, noradrenaline, endogenous opioids, GABA, glutamate, and serotonin (McIntosh and Chick, 2004).
- excitatory and inhibitory neurotransmitters including dopamine, noradrenaline, endogenous opioids, GABA, glutamate, and serotonin (McIntosh and Chick, 2004).
- the promiscuous pharmacological effects of alcohol provide caution in extrapolating from acute drug-alcohol interactions to chronic drug-alcohol interactions.
- ASP8062 did not potentiate the effects of its combined administration with alcohol to the point of ataxia, which is observed with higher blood alcohol exposures. This is possibly due to lower baseline values in treatment with ASP8062 in combination with alcohol and placebo compared with ASP8062 alone and alcohol alone.
- the effect in subjects administered ASP8062 in combination with alcohol was generally no more than two-fold greater than that observed in subjects administered alcohol alone.
- the numerically greater impairment in cognition observed with single doses of ASP8062 combined with alcohol compared with alcohol alone may not be observed with daily administration of ASP8062 and remains to be tested.
- ASP8062 did not affect blood oxygen saturation, including when combined with alcohol. This is a critical feature of ASP8062 as direct receptor agonism by GHB treatment alone decreased oxygen saturation levels and was further decreased when coadministered with ethanol (Thai et al., 2006).
- the current phase 1 study does not suggest risks of a potential interaction between ASP8062 and alcohol precluding future clinical studies in patients with AUD.
- Alcohol had a mild effect on increasing ASP8062 plasma concentration (Cmax but not AUC) and slight impairment on cognitive measurements, but these pharmacodynamic alterations were not observed with ASP8062 treatment alone.
- Cmax but not AUC
- a robust and consistent potentiation of cognitive impairment was not observed with the combination of ASP8062 and alcohol.
- the data from this study provides relevant pharmacokinetic, pharmacodynamic, and safety data to assess the potential risk of coadministration of ASP8062 and alcohol for future studies.
- Example 3 Plasma Pharmacokinetic Parameters of ASP8062 After Administration Alone and in the Presence of Alcohol (Pharmacokinetic Analysis Set, Excluding 1 Outlier)
- Example 3 Table 3. Cogstate Battery Statistical Assessment of Potential Pharmacodynamic Interaction Between ASP8062 and Alcohol
- CI confidence interval
- LS least squares
- CI confidence interval
- LS least squares
- CI confidence interval
- LS least squares
- CI confidence interval
- LS least squares
- Example 3 Table 7. Incidence of Treatment-Related Adverse Events
- %CV coefficient-of-variation percent
- AUCinf area under the concentration-time curve from the time of dosing extrapolated to time infinity
- AUCi as t area under the concentration-time curve from the time of dosing to the last measurable concentration
- CL/F apparent clearance
- C max maximum concentration
- LLOQ lower limit of quantification
- SD standard deviation
- ti/2 half-life
- t max time to peak plasma concentration
- VzF apparent volume of distribution during terminal phase after oral administration.
- CI confidence interval
- LS least squares
- Example 3 Table S6. C-SSRS Categorized Results of ASP8062 and Alcohol (Safety Analysis Set) Abbreviation: C-SSRS, Columbia-Suicide Severity Rating Scale.
- Example 3 Table S7. Percent Blood Oxygen Saturation by Treatment Condition Abbreviation: SD, standard deviation.
- SD standard deviation
- VAS Visual Analogue Scale
- ARCI-49 Addiction Research Center Inventory 49-item questionnaire
- SD standard deviation
- Example 3 Table S10. Alcohol Urge Questionnaire Total Scores of ASP8062 and Alcohol (Safety Analysis Set)
- a novel GAB AB receptor positive allosteric modulator, ASP8062 exerts analgesic effects in a rat model of fibromyalgia. Eur. J. Pharmacol. 865, 172750.
Landscapes
- Health & Medical Sciences (AREA)
- Addiction (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Neurology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurosurgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Psychiatry (AREA)
- Steroid Compounds (AREA)
Abstract
In some embodiments provided herein are methods of treating substance use disorder in a patient in need thereof, the methods comprising administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the substance use disorder and that does not cause respiratory depression in the patient.
Description
Methods of treating substance use disorder
Claim of Priority
This application claims priority under 35 U.S.C. §119(e) to U.S. Patent Application Serial No. 63/237,701, filed on August 27, 2021, the entire contents of which are hereby incorporated by reference.
Field of the Invention
The present disclosure relates to methods for treating that comprise administering the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
Background
Gamma-aminobutyric acid (GABA), the most abundant inhibitory neurotransmitter, activates two families of receptors: ionotropic type A (GABAA) and metabotropic type B (GAB AB) receptors (Olsen, 2002). Activation of GAB AB receptors has demonstrated suppression of drugseeking behavior, analgesic/antinociceptive effects, and anxiolytic activity in animal models and humans (Evenseth et al., 2020; Pin and Prezeau, 2007). Therefore, targeting GAB AB receptor activity may constitute a new therapeutic approach to treatment of neurological and psychiatric disorders, such as substance use disorders, including alcohol and opioid use disorder, fibromyalgia, and depression (Agabio et al., 2012; Evenseth et al., 2020; Foerster et al., 2012). Despite the broad involvement of GAB AB receptor signaling in central nervous system (CNS) function, baclofen is the only GAB AB receptor agonist approved for use as a muscle relaxant and antispastic agent (Evenseth et al., 2020). Although stimulation of GAB AB receptors by baclofen has demonstrated a reduction in addiction-related behaviors in animal models and in patients with alcohol use disorder (AUD) (Addolorato and Leggio, 2010; Agabio et al., 2018; Augier, 2021; Pierce et al., 2018), the clinical use of baclofen is limited by unwanted side effects such as sedation, drowsiness, dizziness, respiratory depression, cognitive impairment, and tolerance from prolonged use (Varani et al., 2014; Vengeliene et al., 2018; Holajova and Franek, 2018). Additionally, pharmacokinetic limitations of baclofen, including low blood-brain barrier (BBB) penetration and short plasma half-life (t1/2) further hinders its effective use for curtailing drug-seeking behavior across different substances of abuse (Evenseth et al., 2020). Therefore, there remains an urgent clinical need for effective and well- tolerated GAB AB receptor activation with a favorable pharmacokinetic profile.
Engagement of GAB AB receptors with an improved pharmacokinetic profile and lower incidence of undesirable side effects may be achieved with positive allosteric modulators (PAMs). In contrast to endogenous neurotransmitters or other agonists, PAMs display little or no intrinsic receptor agonism, but rather enhance the potency and efficacy of endogenous neurotransmitter binding to the orthosteric GAB AB receptor binding site and thus act on the receptor in a more physiological manner (May et al., 2004). The absence of chronic or constitutive GAB AB receptor activation by PAMs may also result in a reduction of the side effects associated with overdosage as well as a reduction in the development of tolerance. While translational findings in preclinical models show alcohol-motivated behaviors to be reduced following treatment with GAB AB PAMS (Maccioni and Colombo, 2019), this reduction occurred at doses lower than those that induced sedation. Furthermore, GAB AB PAM use has shown no indication of any tolerance after repeated treatment. Two separate GAB AB receptor PAMs tested in rat models, CMPPE and ADX71441, both demonstrated suppression of alcohol self-administration and are indicative that GAB AB PAMS share a common feature of attenuating drug-seeking behavior (Augier et al., 2017; Maccioni et al., 2019). However, no GAB AB receptor PAMs under development have been approved for clinical use (Evenseth et al., 2020).
In view of the foregoing, new treatments for substance use disorder would be desirable.
SUMMARY
In some embodiments provided herein are methods of treating substance use disorder in a patient in need thereof, the methods comprising administering to the patient the compound of formula (I):
or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the substance use disorder and that does not cause respiratory depression in the patient.
In some embodiments of the methods, the respiratory depression is determined by measuring the difference, prior to and following administration of the compound of formula (I), in a parameter selected from end tidal CO2, blood oxygen saturation, or respiratory rate.
In some embodiments provided herein are methods of treating substance use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having substance use disorder; and ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the substance use disorder and that does not cause respiratory depression in the patient.
In some embodiments provided herein are methods of treating substance use disorder in a patient in need thereof, the methods comprising: i. determining a first respiratory status in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the substance use disorder; and iii. determining a second respiratory status in the patient; wherein the second respiratory status is not lower than the first respiratory status.
In some embodiments provided herein are methods of treating substance use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having substance use disorder; ii. determining a first respiratory status in the patient; iii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the substance use disorder; and iv. determining a second respiratory status in the patient; wherein the second respiratory status is not lower than the first respiratory status.
In some embodiments provided herein are methods of treating substance use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having substance use disorder; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the substance use disorder; and iii. determining that the administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof, in step ii. does not cause respiratory depression in the patient.
In some embodiments provided herein are methods of treating substance use disorder in a patient in need thereof, the methods comprising administering to the patient the compound of formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the substance use disorder and that does not decrease blood oxygen saturation in the patient.
In some embodiments provided herein are methods of treating substance use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having substance use disorder; and ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the substance use disorder and that does not decrease blood oxygen saturation in the patient.
In some embodiments provided herein are methods of treating substance use disorder in a patient in need thereof, the methods comprising: i. determining a first blood oxygen saturation in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the substance use disorder; and iii. determining a second blood oxygen saturation in the patient; wherein the second blood oxygen saturation is not lower than the first blood oxygen saturation.
In some embodiments provided herein are methods of treating substance use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having substance use disorder; ii. determining a first blood oxygen saturation in the patient; iii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the substance use disorder; and iv. determining a second blood oxygen saturation in the patient; wherein the second blood oxygen saturation is not lower than the first blood oxygen saturation.
In some embodiments provided herein are methods of treating substance use disorder in a patient in need thereof, the methods comprising administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the substance use disorder and that does not increase end tidal CO2 in the patient.
In some embodiments provided herein are methods of treating substance use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having substance use disorder; and ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the substance use disorder and that does not increase end tidal CO2 in the patient.
In some embodiments provided herein are methods of treating substance use disorder in a patient in need thereof, the methods comprising: i. determining a first end tidal CO2 in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the substance use disorder; and iii. determining a second end tidal CO2 in the patient; wherein the second end tidal CO2 is not higher than the first end tidal CO2.
In some embodiments provided herein are methods of treating substance use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having substance use disorder; ii. determining a first end tidal CO2 in the patient; iii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the substance use disorder; and iv. determining a second end tidal CO2 in the patient; wherein the second end tidal CO2 is not higher than the first end tidal CO2.
In some embodiments provided herein are methods of treating substance use disorder in a patient in need thereof, the methods comprising administering to the patient the compound of formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the substance use disorder and that does not decrease respiratory rate in the patient.
In some embodiments provided herein are methods of treating substance use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having substance use disorder; and ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the substance use disorder and that does not decrease respiratory rate in the patient.
In some embodiments provided herein are methods of treating substance use disorder in a patient in need thereof, the methods comprising: i. determining a first respiratory rate in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the substance use disorder; and iii. determining a second respiratory rate in the patient; wherein the second respiratory rate is not lower than the first respiratory rate.
In some embodiments provided herein are methods of treating substance use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having substance use disorder; ii. determining a first respiratory rate in the patient; iii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the substance use disorder; and iv. determining a second respiratory rate in the patient; wherein the second respiratory rate is not lower than the first respiratory rate.
In some embodiments the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is comprised in a pharmaceutical composition which further comprises a pharmaceutically acceptable carrier. Thus, in some embodiments of the methods herein, the patient is administered a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In some embodiments, the substance use disorder relates a use disorder of any abusable substance. In some embodiments, the abusable substance is an opioid, alcohol, nicotine, ***e a ***e derivative, or another drug of abuse such as a benzodiazepine, amphetamine, methamphetamine, and an amphetamine derivative, as well as a dissociative drug such as ketamine, phencyclidine (PCP), and others.
In some embodiments, the substance use disorder is opioid use disorder.
In some embodiments provided herein are methods of treating opioid use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having opioid use disorder; and ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder and that does not cause respiratory depression in the patient.
In some embodiments provided herein are methods of treating opioid use disorder in a patient in
need thereof, the methods comprising: i. determining a first respiratory status in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder; and iii. determining a second respiratory status in the patient; wherein the second respiratory status is not lower than the first respiratory status.
In some embodiments provided herein are methods of treating opioid use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having opioid use disorder; ii. determining a first respiratory status in the patient; iii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder; and iv. determining a second respiratory status in the patient; wherein the second respiratory status is not lower than the first respiratory status.
In some embodiments provided herein are methods of treating opioid use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having opioid use disorder; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder; and iii. determining that the administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof, in step ii. does not cause respiratory depression in the patient.
In some embodiments provided herein are methods of treating opioid use disorder in a patient in need thereof, the methods comprising administering to the patient the compound of formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder and that does not decrease blood oxygen saturation in the patient.
In some embodiments provided herein are methods of treating opioid use disorder in a patient in
need thereof, the methods comprising: i. identifying and/or selecting a patient having opioid use disorder; and ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder and that does not decrease blood oxygen saturation in the patient.
In some embodiments provided herein are methods of treating opioid use disorder in a patient in need thereof, the methods comprising: i. determining a first blood oxygen saturation in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder; and iii. determining a second blood oxygen saturation in the patient; wherein the second blood oxygen saturation is not lower than the first blood oxygen saturation.
In some embodiments provided herein are methods of treating opioid use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having opioid use disorder; ii. determining a first blood oxygen saturation in the patient; iii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder; and iv. determining a second blood oxygen saturation in the patient; wherein the second blood oxygen saturation is not lower than the first blood oxygen saturation.
In some embodiments provided herein are methods of treating opioid use disorder in a patient in need thereof, the methods comprising administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder and that does not increase end tidal CO2 in the patient.
In some embodiments provided herein are methods of treating opioid use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having opioid use disorder; and ii. administering to the patient the compound of Formula (I), or a pharmaceutically
acceptable salt thereof, in an amount that is effective in treating the opioid use disorder and that does not increase end tidal CO2 in the patient.
In some embodiments provided herein are methods of treating opioid use disorder in a patient in need thereof, the methods comprising: i. determining a first end tidal CO2 in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder; and iii. determining a second end tidal CO2 in the patient; wherein the second end tidal CO2 is not higher than the first end tidal CO2.
In some embodiments provided herein are methods of treating opioid use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having opioid use disorder; ii. determining a first end tidal CO2 in the patient; iii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder; and iv. determining a second end tidal CO2 in the patient; wherein the second end tidal CO2 is not higher than the first end tidal CO2.
In some embodiments provided herein are methods of treating opioid use disorder in a patient in need thereof, the methods comprising administering to the patient the compound of formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder and that does not decrease respiratory rate in the patient.
In some embodiments provided herein are methods of treating opioid use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having opioid use disorder; and ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder and that does not decrease respiratory rate in the patient.
In some embodiments provided herein are methods of treating opioid use disorder in a patient in need thereof, the methods comprising: i. determining a first respiratory rate in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder; and iii. determining a second respiratory rate in the patient; wherein the second respiratory rate is not lower than the first respiratory rate.
In some embodiments provided herein are methods of treating opioid use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having opioid use disorder; ii. determining a first respiratory rate in the patient; iii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder; and iv. determining a second respiratory rate in the patient; wherein the second respiratory rate is not lower than the first respiratory rate.
In some embodiments, the substance use disorder is alcohol use disorder.
In some embodiments provided herein are methods of treating alcohol use disorder in a patient in need thereof, the methods comprising administering to the patient the compound of formula (I):
or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol
use disorder and that does not cause respiratory depression in the patient.
In some embodiments of the methods, the respiratory depression is determined by measuring the difference, prior to and following administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof, in a parameter selected from end tidal CO2, blood oxygen saturation, or respiratory rate.
In some embodiments provided herein are methods of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having alcohol use disorder; and ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder and that does not cause respiratory depression in the patient.
In some embodiments provided herein are methods of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. determining a first respiratory status in the patient; iii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder; and ii. determining a second respiratory status in the patient; wherein the second respiratory status is not lower than the first respiratory status.
In some embodiments provided herein are methods of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having alcohol use disorder; ii. determining a first respiratory status in the patient; iv. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder; and iii. determining a second respiratory status in the patient; wherein the second respiratory status is not lower than the first respiratory status.
In some embodiments provided herein are methods of treating alcohol use disorder in a patient
in need thereof, the methods comprising: i. identifying and/or selecting a patient having alcohol use disorder; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder; and iii. determining that the administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof, in step ii. does not cause respiratory depression in the patient.
In some embodiments provided herein are methods of treating alcohol use disorder in a patient in need thereof, the methods comprising administering to the patient the compound of formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder and that does not decrease blood oxygen saturation in the patient.
In some embodiments provided herein are methods of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having alcohol use disorder; and ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder and that does not decrease blood oxygen saturation in the patient.
In some embodiments provided herein are methods of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. determining a first blood oxygen saturation in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder; and iii. determining a second blood oxygen saturation in the patient; wherein the second blood oxygen saturation is not lower than the first blood oxygen saturation.
In some embodiments provided herein are methods of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having alcohol use disorder; ii. determining a first blood oxygen saturation in the patient;
iii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder; and iv. determining a second blood oxygen saturation in the patient; wherein the second blood oxygen saturation is not lower than the first blood oxygen saturation.
In some embodiments provided herein are methods of treating alcohol use disorder in a patient in need thereof, the methods comprising administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder and that does not increase end tidal CO2 in the patient.
In some embodiments provided herein are methods of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having alcohol use disorder; and ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder and that does not increase end tidal CO2 in the patient.
In some embodiments provided herein are methods of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. determining a first end tidal CO2 in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder; and iii. determining a second end tidal CO2 in the patient; wherein the second end tidal CO2 is not higher than the first end tidal CO2.
In some embodiments provided herein are methods of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having alcohol use disorder; ii. determining a first end tidal CO2 in the patient; iii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder; and
iv. determining a second end tidal CO2 in the patient; wherein the second end tidal CO2 is not higher than the first end tidal CO2.
In some embodiments provided herein are methods of treating alcohol use disorder in a patient in need thereof, the methods comprising administering to the patient the compound of formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder and that does not decrease respiratory rate in the patient.
In some embodiments provided herein are methods of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having alcohol use disorder; and ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder and that does not decrease respiratory rate in the patient.
In some embodiments provided herein are methods of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. determining a first respiratory rate in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder; and iii. determining a second respiratory rate in the patient; wherein the second respiratory rate is not lower than the first respiratory rate.
In some embodiments provided herein are methods of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having alcohol use disorder; ii. determining a first respiratory rate in the patient; iii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder; and
iv. determining a second respiratory rate in the patient; wherein the second respiratory rate is not lower than the first respiratory rate.
In some embodiments the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is comprised in a pharmaceutical composition which further comprises a pharmaceutically acceptable carrier. Thus, in some embodiments of the methods herein, the patient is administered a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In some embodiments the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is comprised in a pharmaceutical composition which further comprises a pharmaceutically acceptable carrier. Thus, in some embodiments of the methods herein, the patient is administered a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig- 1- Effects of ASP8062 pretreatment on intravenous self-administration of morphine in rhesus monkeys (Example 2). The mean number of self-administrations and SEM of 3 experiments for the last 3 days are presented. Vehicle: 0.5 w/v% methylcellulose solution (1 mL/kg, intragastric); ASP8062 (1 mL/kg, intragastric); morphine: morphine hydrochloride hydrate (0.03 mg/kg/infusion, 0.25 mL/kg/infusion, intravenous); Saline (0.25 mL/kg/infusion, intravenous). Trial 1 : vehicle/morphine; Trial 2: vehicle/saline; Trial 3: 0.3 mg/kg ASP8062/morphine; Trial 4: 1 mg/kg ASP8062/morphine; Trial 5: 3 mg/kg ASP8062/morphine. *P < 0.05, **P < 0.01, significant difference between Trials 1 and 2 (Student’s t-test). ##P < 0.01, significant difference between Trials 1 and 3 to 5 (William’s test).
Fig- 2. Effect of ASP8062 and morphine on respiratory rate in 3 male cynomolgus monkeys (Example 2). Data show mean ± SD of 3 monkeys. DIW: distilled water sc, Veh: vehicle po, Mor 10: 10 mg/kg morphine sc, ASP 10: 10 mg/kg ASP8062 po.
Fig- 3. Effect of ASP8062 and morphine on tidal volume in 3 male cynomolgus monkeys (Example 2). Data show mean ± SD of 3 monkeys. DIW: distilled water sc, Veh: vehicle po, Mor 10: 10 mg/kg morphine sc, ASP 10: 10 mg/kg ASP8062 po.
Fig- 4. Effect of ASP8062 and morphine on minute volume in 3 male cynomolgus monkeys (Example 2). Data show mean ± SD of 3 monkeys. DIW: distilled water sc, Veh: vehicle po, Mor 10: 10 mg/kg morphine sc, ASP 10: 10 mg/kg ASP8062 po.
Fig- 5. Plasma concentration after oral administration of ASP8062 in male cynomolgus monkeys (Example 2). ASP 3: 3 mg/kg ASP8062 po, ASP 10: 10 mg/kg ASP8062 po. Each point represents the mean of 2 monkeys (10 mg/kg ASP8062 po) or mean ± SD of 3 monkeys (3 mg/kg ASP8062 po).
Fig. 6. Mean plasma concentrati on-time profiles of (A) ASP8062 after administration alone (n=18) and in the presence of alcohol (n=19) (Pharmacokinetic Analysis Set, excluding 1 outlier subject) and (B) ethanol after administration of alcohol alone (n=20) and in the presence of ASP8062 (n=20) (Pharmacokinetic Analysis Set) for the subjects of Example 3.
Fig. 7. Mean Cogstate battery results by treatment for (A) Detection Test to measure psychomotor function, (B) Groton Maze Learning Test (GMLT) to measure executive function, (C) Identification Test to measure attention, and (D) One-Back Test to measure working memory (n=20) for the subjects of Example 3. *One subject was unable to complete the Cogstate tests for the 1.5-hour time point due to adverse events following administration of placebo ASP8062 in combination with alcohol. Error bars represent the standard deviation (SD).
Fig. 8. Mean postural stability test results by treatment (n=20) for the subjects of Example 3.
Fig. 9. Data shown is the oxygen saturation % determined by pulse oximetry % readings for a Phase 1 safety, tolerability, PK, and pharmacodynamic study conducted in a single cohort of 20 healthy subjects with 14 days between individual periods where each subject was tested under each condition for baseline (time 0) and through 12 hours (within-subject paradigm):
■ Placebo or vehicle for both conditions
■ ASP8062 (60 mg po)
■ Alcohol (0.6 g/kg for women; 0.7 g/kg for men)
■ ASP8062 + Alcohol
Notably, ASP8062 + alcohol does not lower oxygen saturation more than alcohol alone for the most part. ASP8062 and placebo appear to largely overlap. The Alcohol as well as the ASP8062 + Alcohol conditions also largely appear to overlap for the most part.
DETAILED DESCRIPTION
Definitions
The compound of formula (I) may also be referred to herein as 6-(4,4-dimethylcyclohexyl)-4- [(1, 1 -di oxo-1 X6-thiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d]pyrimidine. The compound of Formula (I) may also be referred to herein as ASP8062.
The compound of Formula (I) is an orally available GAB AB receptor positive allosteric modulator (PAM). The compound disclosed in, for example, U.S. Patent No 9,051,339, the contents of each of which are incorporated by reference herein in their entirety.
The term “administration” or “administering” refers to a method of providing a dosage of a compound or pharmaceutical composition comprising the compound to a patient. In some embodiments, the patient is a human. In some embodiments, the patient is a non-human mammal. The compositions according to the present invention may be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups and suspensions. Furthermore the compositions containing the therapeutic agents may be administered parenterally, in sterile liquid dosage forms, by transmucosal delivery via solid, liquid or aerosol forms or transdermally via a patch mechanism, cream, lotion or ointment. Various types of transmucosal administration include respiratory tract mucosal administration, nasal mucosal administration, oral transmucosal (such as sublingual and buccal) administration,
and rectal transmucosal administration.
The term “treating” (or “treat” or “treatment”) refers to alleviating, abating or ameliorating a disorder or condition or symptoms thereof, preventing additional symptoms, ameliorating the underlying causes of symptoms, inhibiting the disorder or condition, e.g., arresting the development of the disorder or condition, relieving the disorder or condition, causing regression of the disorder or condition, relieving a condition caused by the disorder or condition, or stopping the symptoms of the disorder or condition therapeutically. For example, the term "treating" in reference to a disorder may include a reduction in severity of one or more symptoms associated with a particular disorder.
In some implementations, the term “treating” as used herein refers to improving or ameliorating an undesired symptom of opioid use disorder or the incidence of opioid use disorder. In some implementations, the treatment reduces the severity of the symptom of opioid use disorder by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, or at least 50%. In some implementations, the treatment reduces the incidence of opioid use disorder by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, or at least 50%. In some implementations, the reduction of severity of a symptom is measured by subjective patient feedback. In some implementations, the reduction of severity of a symptom is measured by objective measurements. In some implementations, the reduction of severity of a symptom is measured by determining the change in the value of a clinical score following administration of the compound of formula (I).
In some embodiments, the methods comprise determining the Cumulative Distribution Function, or CDF, of, for example, the percentage of samples of urine of the patient that are negative for opioids. The CDF provides a way of comparing the overall continuous distribution of percentage of clean urines from a frequency of 0 to a frequency of 100% in an active drug treatment group vs a placebo-treated group. In some implementations, “negative for opioids” means that the patient has at least 80% clean urines by frequency. In some implementations, a urine sample is “negative for opioids” when the amount of opioids in the sample is less than 20% by frequency. The CDF is a statistical function that can be applied to any measurement of frequency of substance abuse including body fluid (i.e., urine or blood sample), self-reporting of substance use, or other measurement (including but not limited to breathalyzer).
As used herein, "patient" refers to any subject, particularly a mammalian subject, for whom diagnosis, prognosis, or therapy is desired, for example, a human.
The terms “treatment regimen” and "dosing regimen" are used interchangeably to refer to the dose and timing of administration of the compound of formula (I).
As used herein, identifying and/or selecting a patient having opioid use disorder refers to identifying the patient; selecting the patient; or both identifying and selecting a patient. In some embodiments of the methods herein, the methods comprise identifying the patient. In some embodiments, the methods comprise selecting the patient. In some embodiments, the methods comprise identifying and selecting the patient.
Reference to "about" a value or parameter herein includes embodiments that are directed to that value or parameter. For example, "about X" includes the disclosure of "X." Unless otherwise specified, the term "about" refers to the indicated value of the variable and to all values of the variable that are within the experimental error of the indicated value or within 10 percent of the indicated value, whichever is greater. Where the term "about" is used within the context of a time period (years, months, weeks, days etc.), the term "about" means that period of time plus or minus one amount of the next subordinate time period (e.g. about 1 year means 11-13 months; about 6 months means 6 months plus or minus 1 week; about 1 week means 6-8 days; etc.), or within 10 percent of the indicated value, whichever is greater.
As used herein, to “decrease blood oxygen saturation” means to decrease blood oxygen saturation by at least 5%, such as at least 10%, such as at least 15%, such as at least 20%. Thus, the blood oxygen saturation does not “decrease” if, following administration of the compound, the blood oxygen saturation value is less than 5% smaller, or not smaller, than prior to administration of the compound.
As used herein, to “increase end tidal CO2” means to increase end tidal CChby at least 10%, such as at least 20%, such as at least 30%, such as at least 40%, such as at least 50%. Thus, the end tidal CO2 does not “increase” if, following administration of the compound, the end tidal CO2 is less than 10% greater, or not greater, than prior to administration of the compound.
As used herein, to “decrease respiratory rate” means to decrease the respiratory rate by at least
5%, such as at least 10%, such as at least 15%, such as at least 20%, such as at least 30%, such as at least 40%, or such as at least 50%. Thus, the compound of formula (I) does not “decrease” the respiratory rate if, following administration of the compound, the respiratory rate decreases by less than 5%, or does not decrease, relative to the respiratory rate prior to administration of the compound.
As used herein, “not lower”, in connection with a second respiratory rate that is “not lower” than the first respiratory rate, means that the second respiratory rate is less than 5% smaller, or not smaller, than the first respiratory rate.
As used herein, “not lower”, in connection with a second blood oxygen saturation that is “not lower” than the first blood oxygen saturation, means that the second blood oxygen saturation is less than 5% smaller, or not smaller, than the first blood oxygen saturation.
As used herein, “not higher”, in connection with a second end tidal CO2 that is “not higher” than the first end tidal CO2, means that the second end tidal CO2 is less than 5% greater, or not greater, than the first end tidal CO2.
As used herein, the terms “suppress” and “depress” (and “suppression” and “depression”) are used interchangeably.
In some embodiments provided herein are methods of treating substance use disorder in a patient in need thereof, the methods comprising administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the substance use disorder and that does not cause respiratory depression in the patient.
In some embodiments provided herein are methods of treating substance use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having substance use disorder; and ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the substance use disorder and that does not cause respiratory depression in the patient.
In some embodiments provided herein are methods of treating substance use disorder in a patient
in need thereof, the methods comprising: i. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the substance use disorder; and ii. determining that the administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof, in step ii. does not cause respiratory depression in the patient.
In some embodiments provided herein are methods of treating substance use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having substance use disorder; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the substance use disorder; and iii. determining that the administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof, in step ii. does not cause respiratory depression in the patient
In some embodiments of the methods, the respiratory depression is determined by measuring the difference, prior to and following administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof, in a parameter selected from end tidal CO2, blood oxygen saturation, or respiratory rate.
In some embodiments provided herein are methods of treating substance use disorder in a patient in need thereof, the methods comprising administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the substance use disorder and that does not decrease blood oxygen saturation in the patient.
In some embodiments provided herein are methods of treating substance use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having substance use disorder; and ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the substance use
disorder and that does not decrease blood oxygen saturation in the patient.
In some embodiments provided herein are methods of treating substance use disorder in a patient in need thereof, the methods comprising: i. determining a first blood oxygen saturation in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the substance use disorder; and iii. determining a second blood oxygen saturation in the patient; wherein the second blood oxygen saturation is not lower than the first blood oxygen saturation.
In some embodiments provided herein are methods of treating substance use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having substance use disorder; ii. determining a first blood oxygen saturation in the patient; iii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the substance use disorder; and iv. determining a second blood oxygen saturation in the patient; wherein the second blood oxygen saturation is not lower than the first blood oxygen saturation.
In some embodiments provided herein are methods of treating substance use disorder in a patient in need thereof, the methods comprising administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the substance use disorder and that does not increase end tidal CO2 in the patient.
In some embodiments provided herein are methods of treating substance use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having substance use disorder; and ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the substance use disorder and that does not increase end tidal CO2 in the patient.
In some embodiments provided herein are methods of treating substance use disorder in a patient
in need thereof, the methods comprising: i. determining a first end tidal CO2 in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the substance use disorder; and iii. determining a second end tidal CO2 in the patient; wherein the second end tidal CO2 is not higher than the first end tidal CO2.
In some embodiments provided herein are methods of treating substance use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having substance use disorder; ii. determining a first end tidal CO2 in the patient; iii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the substance use disorder; and iv. determining a second end tidal CO2 in the patient; wherein the second end tidal CO2 is not higher than the first end tidal CO2.
In some embodiments provided herein are methods of treating substance use disorder in a patient in need thereof, the methods comprising: i. determining a first respiratory rate in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the substance use disorder; and iii. determining a second respiratory rate in the patient; wherein the second respiratory rate is not lower than the first respiratory rate.
In some embodiments provided herein are methods of treating substance use disorder in a patient in need thereof, wherein the patient is being treated with buprenorphine, naxolone, or a combination thereof, the methods comprising administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the substance use disorder and that does not cause respiratory depression in the patient.
In some embodiments provided herein are methods of treating substance use disorder in a
patient in need thereof, the methods comprising administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the substance use disorder and that does not depress respiration in the patient beyond the level of respiratory depression observed with buprenorphine, naxolone, or a combination thereof.
In some embodiments provided herein are methods of treating substance use disorder in a patient in need thereof, the methods comprising: i. treating the patient with buprenorphine, naxolone, or a combination thereof, ii. determining a first respiratory status in the patient; iii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the substance use disorder; and iv. determining a second respiratory status in the patient; wherein the second respiratory status is not lower than the first respiratory status.
In some embodiments provided herein are methods of treating substance use disorder in a patient in need thereof, the methods comprising: i. determining a first respiratory status in the patient; ii. treating the patient with buprenorphine, naxolone, or a combination thereof; iii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the substance use disorder; and iv. determining a second respiratory status in the patient; wherein the second respiratory status is not lower than the first respiratory status.
In some embodiments provided herein are methods of treating substance use disorder in a patient in need thereof, the methods comprising: i. determining a first respiratory rate in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a first amount that is effective in treating the substance use disorder; iii. determining that a second respiratory rate in the patient following the administration is not lower than the first respiratory rate; and
iv. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a second amount that is effective in treating the substance use disorder; wherein the first amount and the second amount are the same or different.
In some embodiments provided herein are methods of treating substance use disorder in a patient in need thereof, the methods comprising: i. determining a first respiratory rate in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a first amount that is effective in treating the substance use disorder; iii. determining that a second respiratory rate in the patient following the administration is lower than the first respiratory rate; and iv. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a second amount that is effective in treating the substance use disorder; wherein the second amount is lower than the first amount.
In some embodiments provided herein are methods of treating substance use disorder in a patient in need thereof, the methods comprising: i. determining a first respiratory rate in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a first amount that is effective in treating the substance use disorder; iii. determining that a second respiratory rate in the patient following the administration is lower than the first respiratory rate; and iv. discontinuing administration of the compound to the patient.
In some embodiments provided herein are methods of treating substance use disorder in a patient in need thereof, the methods comprising: i. determining a first blood oxygen saturation in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a first amount that is effective in treating the substance use disorder;
iii. determining that a second blood oxygen saturation in the patient following the administration is not lower than the first blood oxygen saturation; and iv. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a second amount that is effective in treating the substance use disorder; wherein the first amount and the second amount are the same or different.
In some embodiments provided herein are methods of treating substance use disorder in a patient in need thereof, the methods comprising: i. determining a first blood oxygen saturation in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a first amount that is effective in treating the substance use disorder; iii. determining that a second blood oxygen saturation in the patient following the administration is lower than the first blood oxygen saturation; and iv. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a second amount that is effective in treating the substance use disorder; wherein the second amount is lower than the first amount.
In some embodiments provided herein are methods of treating substance use disorder in a patient in need thereof, the methods comprising: i. determining a first blood oxygen saturation in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a first amount that is effective in treating the substance use disorder; iii. determining that a second blood oxygen saturation in the patient following the administration is lower than the first blood oxygen saturation; and iv. discontinuing administration of the compound to the patient.
In some embodiments provided herein are methods of treating substance use disorder in a patient in need thereof, the methods comprising: i. determining a first end tidal CO2 in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically
acceptable salt thereof, in a first amount that is effective in treating the substance use disorder; iii. determining that a second end tidal CO2 in the patient following the administration is not lower than the first end tidal CO2; and iv. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a second amount that is effective in treating the substance use disorder; wherein the first amount and the second amount are the same or different.
In some embodiments provided herein are methods of treating substance use disorder in a patient in need thereof, the methods comprising: i. determining a first end tidal CO2 in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a first amount that is effective in treating the substance use disorder; iii. determining that a second end tidal CO2 in the patient following the administration is lower than the first end tidal CO2; and iv. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a second amount that is effective in treating the substance use disorder; wherein the second amount is lower than the first amount.
In some embodiments provided herein are methods of treating substance use disorder in a patient in need thereof, the methods comprising: i. determining a first end tidal CO2 in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a first amount that is effective in treating the substance use disorder; iii. determining that a second end tidal CO2 in the patient following the administration is lower than the first end tidal CO2; and iv. discontinuing administration of the compound to the patient.
Some embodiments of the methods of treating substance use disorder disclosed herein comprise measuring the amount or frequency of substance taken by the patient over a period of time prior
to administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof,, and measuring the amount or frequency of substance taken by the patient over an equal period of time following administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof. The amount of substance or the frequency of substance use may also be determined by any clinically suitable method such as evaluation of blood or urine samples (positive/negative or quantitative), or by self-reporting by the patient. Thus, for example, in some embodiments, the methods comprise determining the Cumulative Distribution Function (CDF) of the percentage of breathalyzer samples, or samples of urine or blood of the patient that are negative for substances, as defined herein. Thus, for example, in some embodiments, the methods comprise determining the frequency of substance use on the basis of self-reporting by the patient.
It will be understood that respiratory status can be effectively evaluated via clinical parameters well known to one of ordinary skill in the art, including respiratory rate (which can be observed directly, i.e., visually, or via plethysmography or spirometry), blood oxygen saturation, or end tidal CO2 measurements. As used herein, a recitation that the respiratory status of the patient “is not lower” following treatment is intended to mean that the treatment does not cause respiratory depression.
The substance can be any abusable substance. In addition to opioids, the substance can also be alcohol, nicotine, ***e and ***e derivatives, other drugs of abuse such as benzodiazepines, amphetamines, methamphetamines, and amphetamine derivatives, as well as dissociative drugs such as ketamine, phencyclidine (PCP), and others. Treatment of the substance abuse disorder can be provided as a monotherapy, i.e., the compound of Formula I (or a pharmaceutically acceptable salt thereof) alone, or it can be provided as a combination therapy, i.e., along with one or more other agents such as sodium oxybate (GHB), baclofen, naltrexone or naloxone, and others as described above, and/or with buprenorphine.
In some embodiments provided herein are methods of treating opioid use disorder in a patient in need thereof, the methods comprising administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder and that does not cause respiratory depression in the patient.
In some embodiments provided herein are methods of treating opioid use disorder in a patient in need thereof, the methods comprising:
i. identifying and/or selecting a patient having opioid use disorder; and ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder and that does not cause respiratory depression in the patient.
In some embodiments provided herein are methods of treating opioid use disorder in a patient in need thereof, the methods comprising: i. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder; and ii. determining that the administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof, in step ii. does not cause respiratory depression in the patient.
In some embodiments provided herein are methods of treating opioid use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having opioid use disorder; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder; and iii. determining that the administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof, in step ii. does not cause respiratory depression in the patient
In some embodiments of the methods, the respiratory depression is determined by measuring the difference, prior to and following administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof, in a parameter selected from end tidal CO2, blood oxygen saturation, or respiratory rate.
In some embodiments provided herein are methods of treating opioid use disorder in a patient in need thereof, the methods comprising administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder and that does not decrease blood oxygen saturation in the patient.
In some embodiments provided herein are methods of treating opioid use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having opioid use disorder; and ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder and that does not decrease blood oxygen saturation in the patient.
In some embodiments provided herein are methods of treating opioid use disorder in a patient in need thereof, the methods comprising: i. determining a first blood oxygen saturation in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder; and iii. determining a second blood oxygen saturation in the patient; wherein the second blood oxygen saturation is not lower than the first blood oxygen saturation.
In some embodiments provided herein are methods of treating opioid use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having opioid use disorder; ii. determining a first blood oxygen saturation in the patient; iii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder; and iv. determining a second blood oxygen saturation in the patient; wherein the second blood oxygen saturation is not lower than the first blood oxygen saturation.
In some embodiments provided herein are methods of treating opioid use disorder in a patient in need thereof, the methods comprising administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder and that does not increase end tidal CO2 in the patient.
In some embodiments provided herein are methods of treating opioid use disorder in a patient in need thereof, the methods comprising:
i. identifying and/or selecting a patient having opioid use disorder; and ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder and that does not increase end tidal CO2 in the patient.
In some embodiments provided herein are methods of treating opioid use disorder in a patient in need thereof, the methods comprising: i. determining a first end tidal CO2 in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder; and iii. determining a second end tidal CO2 in the patient; wherein the second end tidal CO2 is not higher than the first end tidal CO2.
In some embodiments provided herein are methods of treating opioid use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having opioid use disorder; ii. determining a first end tidal CO2 in the patient; iii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder; and iv. determining a second end tidal CO2 in the patient; wherein the second end tidal CO2 is not higher than the first end tidal CO2.
In some embodiments provided herein are methods of treating opioid use disorder in a patient in need thereof, the methods comprising: i. determining a first respiratory rate in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder; and iii. determining a second respiratory rate in the patient; wherein the second respiratory rate is not lower than the first respiratory rate.
In some embodiments provided herein are methods of treating opioid use disorder in a patient in
need thereof, wherein the patient is being treated with buprenorphine, naxolone, or a combination thereof, the methods comprising administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder and that does not cause respiratory depression in the patient.
In some embodiments provided herein are methods of treating opioid use disorder in a patient in need thereof, the methods comprising administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder and that does not depress respiration in the patient beyond the level of respiratory depression observed with buprenorphine, naxolone, or a combination thereof.
In some embodiments provided herein are methods of treating opioid use disorder in a patient in need thereof, the methods comprising: i. treating the patient with buprenorphine, naxolone, or a combination thereof, ii. determining a first respiratory status in the patient; iii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder; and iv. determining a second respiratory status in the patient; wherein the second respiratory status is not lower than the first respiratory status.
In some embodiments provided herein are methods of treating opioid use disorder in a patient in need thereof, the methods comprising: i. determining a first respiratory status in the patient; ii. treating the patient with buprenorphine, naxolone, or a combination thereof; iii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder; and iv. determining a second respiratory status in the patient; wherein the second respiratory status is not lower than the first respiratory status.
In some embodiments provided herein are methods of treating opioid use disorder in a patient in need thereof, the methods comprising: i. determining a first respiratory rate in the patient;
ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a first amount that is effective in treating the opioid use disorder; iii. determining that a second respiratory rate in the patient following the administration is not lower than the first respiratory rate; and iv. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a second amount that is effective in treating the opioid use disorder; wherein the first amount and the second amount are the same or different.
In some embodiments provided herein are methods of treating opioid use disorder in a patient in need thereof, the methods comprising: i. determining a first respiratory rate in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a first amount that is effective in treating the opioid use disorder; iii. determining that a second respiratory rate in the patient following the administration is lower than the first respiratory rate; and iv. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a second amount that is effective in treating the opioid use disorder; wherein the second amount is lower than the first amount.
In some embodiments provided herein are methods of treating opioid use disorder in a patient in need thereof, the methods comprising: i. determining a first respiratory rate in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a first amount that is effective in treating the opioid use disorder; iii. determining that a second respiratory rate in the patient following the administration is lower than the first respiratory rate; and iv. discontinuing administration of the compound to the patient.
In some embodiments provided herein are methods of treating opioid use disorder in a patient in
need thereof, the methods comprising: i. determining a first blood oxygen saturation in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a first amount that is effective in treating the opioid use disorder; iii. determining that a second blood oxygen saturation in the patient following the administration is not lower than the first blood oxygen saturation; and iv. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a second amount that is effective in treating the opioid use disorder; wherein the first amount and the second amount are the same or different.
In some embodiments provided herein are methods of treating opioid use disorder in a patient in need thereof, the methods comprising: i. determining a first blood oxygen saturation in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a first amount that is effective in treating the opioid use disorder; iii. determining that a second blood oxygen saturation in the patient following the administration is lower than the first blood oxygen saturation; and iv. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a second amount that is effective in treating the opioid use disorder; wherein the second amount is lower than the first amount.
In some embodiments provided herein are methods of treating opioid use disorder in a patient in need thereof, the methods comprising: i. determining a first blood oxygen saturation in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a first amount that is effective in treating the opioid use disorder; iii. determining that a second blood oxygen saturation in the patient following the administration is lower than the first blood oxygen saturation; and iv. discontinuing administration of the compound to the patient.
In some embodiments provided herein are methods of treating opioid use disorder in a patient in need thereof, the methods comprising: i. determining a first end tidal CO2 in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a first amount that is effective in treating the opioid use disorder; iii. determining that a second end tidal CO2 in the patient following the administration is not lower than the first end tidal CO2; and iv. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a second amount that is effective in treating the opioid use disorder; wherein the first amount and the second amount are the same or different.
In some embodiments provided herein are methods of treating opioid use disorder in a patient in need thereof, the methods comprising: i. determining a first end tidal CO2 in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a first amount that is effective in treating the opioid use disorder; iii. determining that a second end tidal CO2 in the patient following the administration is lower than the first end tidal CO2; and iv. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a second amount that is effective in treating the opioid use disorder; wherein the second amount is lower than the first amount.
In some embodiments provided herein are methods of treating opioid use disorder in a patient in need thereof, the methods comprising: i. determining a first end tidal CO2 in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a first amount that is effective in treating the opioid use disorder; iii. determining that a second end tidal CO2 in the patient following the administration is
lower than the first end tidal CO2; and iv. discontinuing administration of the compound to the patient.
The opioid can be any abusable opioid. In some embodiments, the opioid is diacetylmorphine or heroin, fentanyl, carfentanil, hydrocodone, hydromorphone, meperidine, methadone, morphine and metabolites, oxycodone, oxymorphone, propoxyphene, or tramadol. In certain embodiments, the opioid is selected from the group of morphine and its metabolites, fentanyl, heroin, and oxycodone. In some embodiments, the opioid is morphine. In some embodiments, the opioid is fentanyl. Treatment of the opioid use disorder can be provided as a monotherapy, i.e., the compound of Formula I (or a pharmaceutically acceptable salt thereof) alone, or it can be provided as a combination therapy, i.e., along with one or more other agents used for treating opioid use disorder such as methadone, sodium oxybate (GHB), baclofen, naltrexone or naloxone, suboxone, and/or with buprenorphine.
Some embodiments of the methods disclosed herein comprise measuring the amount or frequency of opioid taken by the patient over a period of time prior to administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof, and measuring the amount or frequency of opioid taken by the patient over an equal period of time following administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof. The amount of opioid or the frequency of opioid use may also be determined by any clinically suitable method such as evaluation of blood or urine samples (positive/negative or quantitative), or by self-reporting by the patient. Thus, for example, in some embodiments, the methods comprise determining the Cumulative Distribution Function (CDF) of the percentage of samples of urine of the patient that are negative for opioids, as defined herein. Thus, for example, in some embodiments, the methods comprise determining the frequency of opioid use on the basis of self-reporting by the patient.
In some embodiments provided herein are methods of treating alcohol use disorder in a patient in need thereof, the methods comprising administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder and that does not cause respiratory depression in the patient.
In some embodiments provided herein are methods of treating alcohol use disorder in a patient in need thereof, the methods comprising:
i. identifying and/or selecting a patient having alcohol use disorder; and ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder and that does not cause respiratory depression in the patient.
In some embodiments provided herein are methods of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder; and ii. determining that the administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof, in step ii. does not cause respiratory depression in the patient.
In some embodiments provided herein are methods of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having alcohol use disorder; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder; and iii. determining that the administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof, in step ii. does not cause respiratory depression in the patient
In some embodiments of the methods, the respiratory depression is determined by measuring the difference, prior to and following administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof, in a parameter selected from end tidal CO2, blood oxygen saturation, or respiratory rate.
In some embodiments provided herein are methods of treating alcohol use disorder in a patient in need thereof, the methods comprising administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder and that does not decrease blood oxygen saturation in the patient.
In some embodiments provided herein are methods of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having alcohol use disorder; and ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder and that does not decrease blood oxygen saturation in the patient.
In some embodiments provided herein are methods of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. determining a first blood oxygen saturation in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder; and iii. determining a second blood oxygen saturation in the patient; wherein the second blood oxygen saturation is not lower than the first blood oxygen saturation.
In some embodiments provided herein are methods of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having alcohol use disorder; ii. determining a first blood oxygen saturation in the patient; iii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder; and iv. determining a second blood oxygen saturation in the patient; wherein the second blood oxygen saturation is not lower than the first blood oxygen saturation.
In some embodiments provided herein are methods of treating alcohol use disorder in a patient in need thereof, the methods comprising administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder and that does not increase end tidal CO2 in the patient.
In some embodiments provided herein are methods of treating alcohol use disorder in a patient
in need thereof, the methods comprising: i. identifying and/or selecting a patient having alcohol use disorder; and ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder and that does not increase end tidal CO2 in the patient.
In some embodiments provided herein are methods of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. determining a first end tidal CO2 in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder; and iii. determining a second end tidal CO2 in the patient; wherein the second end tidal CO2 is not higher than the first end tidal CO2.
In some embodiments provided herein are methods of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having alcohol use disorder; ii. determining a first end tidal CO2 in the patient; iii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder; and iv. determining a second end tidal CO2 in the patient; wherein the second end tidal CO2 is not higher than the first end tidal CO2.
In some embodiments provided herein are methods of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. determining a first respiratory rate in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder; and iii. determining a second respiratory rate in the patient; wherein the second respiratory rate is not lower than the first respiratory rate.
In some embodiments provided herein are methods of treating alcohol use disorder in a patient in need thereof, wherein the patient is being treated with buprenorphine, naxolone, or a combination thereof, the methods comprising administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder and that does not cause respiratory depression in the patient.
In some embodiments provided herein are methods of treating alcohol use disorder in a patient in need thereof, the methods comprising administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder and that does not depress respiration in the patient beyond the level of respiratory depression observed with buprenorphine, naxolone, or a combination thereof.
In some embodiments provided herein are methods of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. treating the patient with buprenorphine, naxolone, or a combination thereof, ii. determining a first respiratory status in the patient; iii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder; and iv. determining a second respiratory status in the patient; wherein the second respiratory status is not lower than the first respiratory status.
In some embodiments provided herein are methods of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. determining a first respiratory status in the patient; ii. treating the patient with buprenorphine, naxolone, or a combination thereof; iii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder; and iv. determining a second respiratory status in the patient; wherein the second respiratory status is not lower than the first respiratory status.
In some embodiments provided herein are methods of treating alcohol use disorder in a patient in need thereof, the methods comprising:
i. determining a first respiratory rate in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a first amount that is effective in treating the alcohol use disorder; iii. determining that a second respiratory rate in the patient following the administration is not lower than the first respiratory rate; and iv. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a second amount that is effective in treating the alcohol use disorder; wherein the first amount and the second amount are the same or different.
In some embodiments provided herein are methods of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. determining a first respiratory rate in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a first amount that is effective in treating the alcohol use disorder; iii. determining that a second respiratory rate in the patient following the administration is lower than the first respiratory rate; and iv. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a second amount that is effective in treating the alcohol use disorder; wherein the second amount is lower than the first amount.
In some embodiments provided herein are methods of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. determining a first respiratory rate in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a first amount that is effective in treating the alcohol use disorder; iii. determining that a second respiratory rate in the patient following the administration is lower than the first respiratory rate; and iv. discontinuing administration of the compound to the patient.
In some embodiments provided herein are methods of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. determining a first blood oxygen saturation in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a first amount that is effective in treating the alcohol use disorder; iii. determining that a second blood oxygen saturation in the patient following the administration is not lower than the first blood oxygen saturation; and iv. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a second amount that is effective in treating the alcohol use disorder; wherein the first amount and the second amount are the same or different.
In some embodiments provided herein are methods of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. determining a first blood oxygen saturation in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a first amount that is effective in treating the alcohol use disorder; iii. determining that a second blood oxygen saturation in the patient following the administration is lower than the first blood oxygen saturation; and iv. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a second amount that is effective in treating the alcohol use disorder; wherein the second amount is lower than the first amount.
In some embodiments provided herein are methods of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. determining a first blood oxygen saturation in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a first amount that is effective in treating the alcohol use disorder; iii. determining that a second blood oxygen saturation in the patient following the administration is lower than the first blood oxygen saturation; and
iv. discontinuing administration of the compound to the patient.
In some embodiments provided herein are methods of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. determining a first end tidal CO2 in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a first amount that is effective in treating the alcohol use disorder; iii. determining that a second end tidal CO2 in the patient following the administration is not lower than the first end tidal CO2; and iv. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a second amount that is effective in treating the alcohol use disorder; wherein the first amount and the second amount are the same or different.
In some embodiments provided herein are methods of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. determining a first end tidal CO2 in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a first amount that is effective in treating the alcohol use disorder; iii. determining that a second end tidal CO2 in the patient following the administration is lower than the first end tidal CO2; and iv. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a second amount that is effective in treating the alcohol use disorder; wherein the second amount is lower than the first amount.
In some embodiments provided herein are methods of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. determining a first end tidal CO2 in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a first amount that is effective in treating the alcohol use disorder;
iii. determining that a second end tidal CO2 in the patient following the administration is lower than the first end tidal CO2; and iv. discontinuing administration of the compound to the patient.
Some embodiments of the methods of treating alcohol use disorder disclosed herein comprise measuring the amount or frequency of alcohol taken by the patient over a period of time prior to administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof, and measuring the amount or frequency of alcohol taken by the patient over an equal period of time following administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof,. The amount of alcohol or the frequency of alcohol use may also be determined by any clinically suitable method such as breathalyzer, or evaluation of blood or urine samples (positive/negative or quantitative), or by self-reporting by the patient. Thus, for example, in some embodiments, the methods comprise determining the Cumulative Distribution Function (CDF) of the percentage of breathalyzer samples, or samples of blood of the patient that are negative for alcohols, as defined herein. Thus, for example, in some embodiments, the methods comprise determining the frequency of alcohol use on the basis of self-reporting by the patient.
It will be understood that respiratory status can be effectively evaluated via clinical parameters well known to one of ordinary skill in the art, including respiratory rate (which can be observed directly, i.e., visually, or via plethysmography or spirometry), blood oxygen saturation, or end tidal CO2 measurements. As used herein, a recitation that the respiratory status of the patient “is not lower” following treatment is intended to mean that the treatment does not cause respiratory depression.
The alcohol can be any abusable alcohol. Treatment of the alcohol use disorder can be provided as a monotherapy, i.e., the compound of Formula I (or a pharmaceutically acceptable salt thereof) alone, or it can be provided as a combination therapy, i.e., along with one or more other agents suitable for treating alcohol use disorder or substance abuse disorder generally.
In some embodiments, the method comprises administering the compound of Formula I, or a pharmaceutically acceptable salt thereof, to a patient daily.
In some embodiments, the amount administered is titrated from a lower dose to a higher dose over a period of time. In some embodiments, the amount administered is titrated from a higher
dose to a lower dose over a period of time.
In some embodiments, the methods comprise: i. administering a first amount of the compound of Formula (I) or a pharmaceutically acceptable salt thereof daily over a period of time; ii. determining the respiratory rate in the patient after the period of time; and iii. administering a second amount that is greater than the first amount of the compound of Formula (I) or a pharmaceutically acceptable salt thereof daily over a second period of time that is the same as the first period of time.
In some embodiments, the methods comprise: i. administering a first amount of the compound of Formula (I) or a pharmaceutically acceptable salt thereof daily over a period of time; ii. determining the respiratory rate in the patient after the period of time; and iii. administering a second amount that is smaller than the first amount of the compound of Formula (I) or a pharmaceutically acceptable salt thereof daily over a second period of time that is the same as the first period of time.
In some embodiments, the methods comprise: i. administering a first amount of the compound of Formula (I) or a pharmaceutically acceptable salt thereof daily over a period of time; ii. determining the respiratory rate in the patient after the period of time; and iii. administering a second amount that is the same as the first amount of the compound of Formula (I) or a pharmaceutically acceptable salt thereof daily over a second period of time that is the same as the first period of time.
In some embodiments, a method as provided herein comprises administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a patient over a period of time. The period of time may be, for example, based on one or more of: the stage of disease in the patient, the mass and sex of the patient, age of the patient, clinical trial guidelines, and information on the approved drug label if applicable. In some embodiments, a suitable period of time can be from 1 week to 2 years, such as 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 12 weeks, 3 months, 24 weeks, 6 months, 12 months, 18 months, or 2 years, or any value in between. In other embodiments, a suitable period of time can be from 1 month to 10 years, for example, 1 month,
6 months, 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or 10 years, or any value in between.
In some embodiments, the compound of Formula (I) or pharmaceutically acceptable salt thereof is administered in an amount equal to about 6.25 mg to about 50 mg per day , such as about 12.5 mg per day to about 37.5 mg per day, such as about 25 mg per day. In some embodiments, the compound of Formula (I) or pharmaceutically acceptable salt thereof is administered in an amount equal to about 5 mg to about 100 mg per day, such as about 5 mg per day, about 10 mg per day, about 15 mg per day, about 20 mg per day, about 25 mg per day, about 30 mg per day, about 35 mg per day, about 40 mg per day, or about 50 mg per day.
In some embodiments case the amount per day is administered in one daily dose equal to the total amount per day. In some embodiments case the amount per day is administered in two daily doses, each equal to half of the total amount per day. For example, an amount of 25 mg per day of the compound of formula (I), or a pharmaceutically acceptable salt thereof, may be administered in one dose of 25 mg per day, or in two doses each of 12.5 mg per day, or in three doses each of 8.33 mg per day. For example, an amount of 30 mg per day of the compound of formula (I), or a pharmaceutically acceptable salt thereof, may be administered in one dose of 30 mg per day, or in two doses each of 15 mg per day, or in three doses each of 10 mg per day. For example, an amount of 60 mg per day of the compound of formula (I), or a pharmaceutically acceptable salt thereof, may be administered in one dose of 50 mg per day, or in two doses each of 30 mg per day, or in three doses each of 20 mg per day. The dosage, or the dosage per day, may differ between the different clinical visits or visits to a medical practitioner based on an observation or measurement of the severity of the disorder or condition being treated.
It will be understood that respiratory status can be effectively evaluated via clinical parameters well known to one of ordinary skill in the art, including respiratory rate (which can be observed directly, i.e., visually, or via plethysmography or spirometry), blood oxygen saturation, or end tidal CO2 measurements. As used herein, a recitation that the respiratory status of the patient “is not lower” following treatment is intended to mean that the treatment does not cause respiratory depression.
In some embodiments provided herein is a compound of Formula (I) or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I)
or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, for use in treatment of a patient with substance use disorder. In some embodiments the compound of Formula (I) or pharmaceutically acceptable salt thereof, or the pharmaceutical composition, is administered to the patient orally. In some embodiments, the compound of Formula (I) or pharmaceutically acceptable salt thereof, or the pharmaceutical composition, is administered to the patient in an amount from about 6.25 mg to about 50 mg per day, such as about 12.5 mg per day to about 37.5 mg per day, such as about 25 mg per day. In some embodiments the compound of Formula (I) or pharmaceutically acceptable salt thereof, or the pharmaceutical composition, is administered to the patient orally in an amount from about 6.25 mg to about 50 mg per day, such as about 12.5 mg per day to about 37.5 mg per day, such as about 25 mg per day. In some embodiments, the compound of Formula (I) or pharmaceutically acceptable salt thereof is administered in an amount equal to about 5 mg to about 100 mg per day, such as about 5 mg per day, about 10 mg per day, about 15 mg per day, about 20 mg per day, about 25 mg per day, about 30 mg per day, about 35 mg per day, about 40 mg per day, or about 50 mg per day. In some embodiments, the compound of Formula (I) or pharmaceutically acceptable salt thereof is administered orally in an amount equal to about 5 mg to about 100 mg per day, such as about 5 mg per day, about 10 mg per day, about 15 mg per day, about 20 mg per day, about 25 mg per day, about 30 mg per day, about 35 mg per day, about 40 mg per day, or about 50 mg per day.
In some embodiments provided herein is the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating substance use disorder in a patient in need thereof, the methods comprising administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the substance use disorder and that does not cause respiratory depression in the patient.
In some embodiments provided herein is the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating substance use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having substance use disorder; and ii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the substance use disorder and that does not cause respiratory depression in the patient.
In some embodiments provided herein is the compound of Formula (I), or a pharmaceutically
acceptable salt thereof, for use in a method of treating substance use disorder in a patient in need thereof, the methods comprising: i. determining a first respiratory status in the patient; ii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the substance use disorder; and iii. determining a second respiratory status in the patient; wherein the second respiratory status is not lower than the first respiratory status.
In some embodiments provided herein is the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating substance use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having or susceptible to substance use disorder; ii. determining a first respiratory status in the patient; iii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the substance use disorder; and iv. determining a second respiratory status in the patient; wherein the second respiratory status is not lower than the first respiratory status.
In some embodiments provided herein is the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating substance use disorder in a patient in need thereof, the methods comprising administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the substance use disorder and that does not decrease blood oxygen saturation in the patient.
In some embodiments provided herein is the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating substance use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having substance use disorder; and ii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the substance use disorder and that does not decrease blood oxygen saturation in the patient.
In some embodiments provided herein is the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating substance use disorder in a patient in need thereof, the methods comprising: i. determining a first blood oxygen saturation in the patient; ii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the substance use disorder; and iii. determining a second blood oxygen saturation in the patient; wherein the second blood oxygen saturation is not lower than the first blood oxygen saturation.
In some embodiments provided herein is the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating substance use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having substance use disorder; ii. determining a first blood oxygen saturation in the patient; iii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the substance use disorder; and iv. determining a second blood oxygen saturation in the patient; wherein the second blood oxygen saturation is not lower than the first blood oxygen saturation.
In some embodiments provided herein is the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating substance use disorder in a patient in need thereof, the methods comprising administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the substance use disorder and that does not increase end tidal CO2 in the patient.
In some embodiments provided herein is the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating substance use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having substance use disorder; and ii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the substance use disorder and
that does not increase end tidal CO2 in the patient.
In some embodiments provided herein is the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating substance use disorder in a patient in need thereof, the methods comprising: i. determining a first end tidal CO2 in the patient; ii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the substance use disorder; and iii. determining a second end tidal CO2 in the patient; wherein the second end tidal CO2 is not higher than the first end tidal CO2.
In some embodiments provided herein is the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating substance use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having substance use disorder; ii. determining a first end tidal CO2 in the patient; iii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the substance use disorder; and iv. determining a second end tidal CO2 in the patient; wherein the second end tidal CO2 is not higher than the first end tidal CO2.
In some embodiments provided herein is the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating substance use disorder in a patient in need thereof, the methods comprising: i. determining a first respiratory rate in the patient; ii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the substance use disorder; and iii. determining a second respiratory rate in the patient; wherein the second respiratory rate is not lower than the first respiratory rate.
In some embodiments provided herein is the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating substance use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having substance use disorder;
ii. determining a first respiratory rate in the patient; iii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the substance use disorder; and iv. determining a second respiratory rate in the patient; wherein the second respiratory rate is not lower than the first respiratory rate.
In some embodiments provided herein is a use of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating substance use disorder in a patient in need thereof, in an amount that is effective in treating the substance use disorder and that does not cause respiratory depression in the patient.
In some embodiments provided herein is a use of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating substance use disorder in a patient in need thereof, wherein the patient has been identified and/or selected as having substance use disorder, in an amount that is effective in treating the substance use disorder and that does not cause respiratory depression in the patient.
In some embodiments provided herein is a use of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating substance use disorder in a patient in need thereof, wherein a first respiratory status is determined in the patient prior to administration of the medicament and a second respiratory status is determined in the patient after administration of the medicament, in an amount that is effective in treating the substance use disorder, wherein the second respiratory status is not lower than the first respiratory status.
In some embodiments provided herein is a use of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating substance use disorder in a patient in need thereof, wherein the patient has been identified and/or selected as having substance use disorder, wherein a first respiratory status is determined in the patient prior to administration of the medicament and a second respiratory status is determined in the patient after administration of the medicament, in an amount that is effective in treating the substance use disorder, wherein the second respiratory status is not lower than the first respiratory status.
In some embodiments provided herein is a use of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating substance use disorder in a patient in need thereof, in an amount that is effective in treating the substance use disorder and that does not decrease blood oxygen saturation in the patient.
In some embodiments provided herein is a use of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating substance use disorder in a patient in need thereof, wherein the patient has been identified and/or selected as having substance use disorder, in an amount that is effective in treating the substance use disorder and that does not decrease blood oxygen saturation in the patient.
In some embodiments provided herein is a use of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating substance use disorder in a patient in need thereof, wherein a first blood oxygen saturation is determined in the patient prior to administration of the medicament and a second blood oxygen saturation is determined in the patient after administration of the medicament, in an amount that is effective in treating the substance use disorder, wherein the second blood oxygen saturation is not lower than the first blood oxygen saturation.
In some embodiments provided herein is a use of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating substance use disorder in a patient in need thereof, wherein the patient has been identified and/or selected as having substance use disorder, wherein a first blood oxygen saturation is determined in the patient prior to administration of the medicament and a second blood oxygen saturation is determined in the patient after administration of the medicament, in an amount that is effective in treating the substance use disorder; wherein the second blood oxygen saturation is not lower than the first blood oxygen saturation.
In some embodiments provided herein is a use of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating substance use disorder in a patient in need thereof, in an amount that is effective in treating the substance use disorder and that does not increase end tidal CO2 in the patient.
In some embodiments provided herein is a use of the compound of Formula (I), or a
pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating substance use disorder in a patient in need thereof, wherein the patient has been identified and/or selected as having substance use disorder, in an amount that is effective in treating the substance use disorder and that does not increase end tidal CO2 in the patient.
In some embodiments provided herein is the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating substance use disorder in a patient in need thereof, wherein a first end tidal CO2 is determined in the patient prior to administration of the medicament and a second first end tidal CO2 is determined in the patient after administration of the medicament, in an amount that is effective in treating the substance use disorder, wherein the second end tidal CO2 is not higher than the first end tidal CO2.
In some embodiments provided herein is a use of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating substance use disorder in a patient in need thereof, wherein the patient has been identified and/or selected as having substance use disorder, wherein a first end tidal CO2 is determined in the patient prior to administration of the medicament and a second first end tidal CO2 is determined in the patient after administration of the medicament, in an amount that is effective in treating the substance use disorder, wherein the second end tidal CO2 is not higher than the first end tidal CO2.
In some embodiments provided herein is a use of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating substance use disorder in a patient in need thereof, wherein a first respiratory rate is determined in the patient prior to administration of the medicament and a second respiratory rate is determined in the patient after administration of the medicament, in an amount that is effective in treating the substance use disorder, wherein the second respiratory rate is not lower than the first respiratory rate.
In some embodiments provided herein is the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating substance use disorder in a patient in need thereof, wherein the patient has been identified and/or selected as having substance use disorder, wherein a first respiratory rate is determined in the patient prior to
administration of the medicament and a second respiratory rate is determined in the patient after administration of the medicament, in an amount that is effective in treating the substance use disorder; wherein the second respiratory rate is not lower than the first respiratory rate.
The severity of substance use disorder may be determined, for example, by measuring the value of a clinical score associated with the substance use disorder. Similarly, in some embodiments, the effectiveness of the treatment of substance use disorder may be determined, for example, by measuring the value of a clinical score associated with the substance use disorder following the treatment. Accordingly, in some embodiments, a method of treatment disclosed herein comprises determining the value for the patient of a clinical score associated with the substance use disorder. In some embodiments, the method comprises determining that the value of the clinical score at a time point following administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof, is different from the value of the clinical score prior to or at the time of administration.
In some embodiments, the severity of the clinical score is determined by one or more criteria defined in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (also known as DSM-5), incorporated herein in its entirety. In some embodiments, the severity of the clinical score is determined in accordance with the patient global impression severity scale (also known as PGIS), incorporated herein in its entirety. In some embodiments, the severity of the clinical score is determined in accordance with the clinician global impression severity scale (also known as CGIS), incorporated herein in its entirety.
The effect of treatment with the compound of formula (I) may be determined, for example, by measuring the reduction in the severity of a symptom of the substance use disorder. Thus, in some embodiments, provided herein are methods as disclosed herein, wherein the method reduces the severity of a symptom of the substance use disorder by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35% or at least 40%. Thus, in some embodiments, provided herein are methods as disclosed herein, wherein the decrease in respiratory rate following administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof, is reduced by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35% or at least 40% relative to the decrease in respiratory rate prior to administration.
In some embodiments provided herein is a compound of Formula (I) or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, for use in treatment of a patient with alcohol use disorder. In some embodiments the compound of Formula (I) or pharmaceutically acceptable salt thereof, or the pharmaceutical composition, is administered to the patient orally. In some embodiments, the compound of Formula (I) or pharmaceutically acceptable salt thereof, or the pharmaceutical composition, is administered to the patient in an amount from about 6.25 mg to about 50 mg per day. In some embodiments the compound of Formula (I) or pharmaceutically acceptable salt thereof, or the pharmaceutical composition, is administered to the patient orally in an amount from about 6.25 mg to about 50 mg per day.
In some embodiments provided herein is a compound of Formula (I) or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, for use in treatment of a patient with opioid use disorder. In some embodiments the compound of Formula (I) or pharmaceutically acceptable salt thereof, or the pharmaceutical composition, is administered to the patient orally. In some embodiments, the compound of Formula (I) or pharmaceutically acceptable salt thereof, or the pharmaceutical composition, is administered to the patient in an amount from about 6.25 mg to about 50 mg per day. In some embodiments the compound of Formula (I) or pharmaceutically acceptable salt thereof, or the pharmaceutical composition, is administered to the patient orally in an amount from about 6.25 mg to about 50 mg per day, such as about 12.5 mg per day to about 37.5 mg per day, such as about 25 mg per day. In some embodiments the compound of Formula (I) or pharmaceutically acceptable salt thereof, or the pharmaceutical composition, is administered to the patient orally in an amount from about 6.25 mg to about 50 mg per day, such as about 12.5 mg per day to about 37.5 mg per day, such as about 25 mg per day. In some embodiments, the compound of Formula (I) or pharmaceutically acceptable salt thereof is administered in an amount equal to about 5 mg to about 100 mg per day, such as about 5 mg per day, about 10 mg per day, about 15 mg per day, about 20 mg per day, about 25 mg per day, about 30 mg per day, about 35 mg per day, about 40 mg per day, or about 50 mg per day. In some embodiments, the compound of Formula (I) or pharmaceutically acceptable salt thereof is administered orally in an amount equal to about 5 mg to about 100 mg per day, such as about 5 mg per day, about 10 mg per day, about 15 mg per day, about 20 mg per day, about 25 mg per day, about 30 mg per day, about 35 mg per day, about 40
mg per day, or about 50 mg per day.
In some embodiments provided herein is the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating opioid use disorder in a patient in need thereof, the methods comprising administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the opioid use disorder and that does not cause respiratory depression in the patient.
In some embodiments provided herein is the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating opioid use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having opioid use disorder; and ii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the opioid use disorder and that does not cause respiratory depression in the patient.
In some embodiments provided herein is the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating opioid use disorder in a patient in need thereof, the methods comprising: i. determining a first respiratory status in the patient; ii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the opioid use disorder; and iii. determining a second respiratory status in the patient; wherein the second respiratory status is not lower than the first respiratory status.
In some embodiments provided herein is the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating opioid use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having or susceptible to opioid use disorder; ii. determining a first respiratory status in the patient; iii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the opioid use disorder; and iv. determining a second respiratory status in the patient; wherein the second respiratory status is not lower than the first respiratory status.
In some embodiments provided herein is the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating opioid use disorder in a patient in need thereof, the methods comprising administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the opioid use disorder and that does not decrease blood oxygen saturation in the patient.
In some embodiments provided herein is the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating opioid use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having opioid use disorder; and ii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the opioid use disorder and that does not decrease blood oxygen saturation in the patient.
In some embodiments provided herein is the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating opioid use disorder in a patient in need thereof, the methods comprising: i. determining a first blood oxygen saturation in the patient; ii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the opioid use disorder; and iii. determining a second blood oxygen saturation in the patient; wherein the second blood oxygen saturation is not lower than the first blood oxygen saturation.
In some embodiments provided herein is the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating opioid use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having opioid use disorder; ii. determining a first blood oxygen saturation in the patient; iii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the opioid use disorder; and iv. determining a second blood oxygen saturation in the patient; wherein the second blood oxygen saturation is not lower than the first blood oxygen saturation.
In some embodiments provided herein is the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating opioid use disorder in a patient in need thereof, the methods comprising administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the opioid use disorder and that does not increase end tidal CO2 in the patient.
In some embodiments provided herein is the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating opioid use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having opioid use disorder; and ii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the opioid use disorder and that does not increase end tidal CO2 in the patient.
In some embodiments provided herein is the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating opioid use disorder in a patient in need thereof, the methods comprising: i. determining a first end tidal CO2 in the patient; ii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the opioid use disorder; and iii. determining a second end tidal CO2 in the patient; wherein the second end tidal CO2 is not higher than the first end tidal CO2.
In some embodiments provided herein is the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating opioid use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having opioid use disorder; ii. determining a first end tidal CO2 in the patient; iii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the opioid use disorder; and iv. determining a second end tidal CO2 in the patient; wherein the second end tidal CO2 is not higher than the first end tidal CO2.
In some embodiments provided herein is the compound of Formula (I), or a pharmaceutically
acceptable salt thereof, for use in a method of treating opioid use disorder in a patient in need thereof, the methods comprising: i. determining a first respiratory rate in the patient; ii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the opioid use disorder; and iii. determining a second respiratory rate in the patient; wherein the second respiratory rate is not lower than the first respiratory rate.
In some embodiments provided herein is the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating opioid use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having opioid use disorder; ii. determining a first respiratory rate in the patient; iii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the opioid use disorder; and iv. determining a second respiratory rate in the patient; wherein the second respiratory rate is not lower than the first respiratory rate.
In some embodiments provided herein is a use of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating opioid use disorder in a patient in need thereof, in an amount that is effective in treating the opioid use disorder and that does not cause respiratory depression in the patient.
In some embodiments provided herein is a use of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating opioid use disorder in a patient in need thereof, wherein the patient has been identified and/or selected as having opioid use disorder, in an amount that is effective in treating the opioid use disorder and that does not cause respiratory depression in the patient.
In some embodiments provided herein is a use of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating opioid use disorder in a patient in need thereof, wherein a first respiratory status is determined in the patient prior to administration of the medicament and a second respiratory status is determined in the patient after administration of the medicament, in an amount that is effective in treating the
opioid use disorder, wherein the second respiratory status is not lower than the first respiratory status.
In some embodiments provided herein is a use of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating opioid use disorder in a patient in need thereof, wherein the patient has been identified and/or selected as having opioid use disorder, wherein a first respiratory status is determined in the patient prior to administration of the medicament and a second respiratory status is determined in the patient after administration of the medicament, in an amount that is effective in treating the opioid use disorder, wherein the second respiratory status is not lower than the first respiratory status.
In some embodiments provided herein is a use of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating opioid use disorder in a patient in need thereof, in an amount that is effective in treating the opioid use disorder and that does not decrease blood oxygen saturation in the patient.
In some embodiments provided herein is a use of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating opioid use disorder in a patient in need thereof, wherein the patient has been identified and/or selected as having opioid use disorder, in an amount that is effective in treating the opioid use disorder and that does not decrease blood oxygen saturation in the patient.
In some embodiments provided herein is a use of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating opioid use disorder in a patient in need thereof, wherein a first blood oxygen saturation is determined in the patient prior to administration of the medicament and a second blood oxygen saturation is determined in the patient after administration of the medicament, in an amount that is effective in treating the opioid use disorder, wherein the second blood oxygen saturation is not lower than the first blood oxygen saturation.
In some embodiments provided herein is a use of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating opioid use disorder in a patient in need thereof, wherein the patient has been identified and/or selected as having opioid use disorder, wherein a first blood oxygen saturation is determined in the patient
prior to administration of the medicament and a second blood oxygen saturation is determined in the patient after administration of the medicament, in an amount that is effective in treating the opioid use disorder; wherein the second blood oxygen saturation is not lower than the first blood oxygen saturation.
In some embodiments provided herein is a use of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating opioid use disorder in a patient in need thereof, in an amount that is effective in treating the opioid use disorder and that does not increase end tidal CO2 in the patient.
In some embodiments provided herein is a use of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating opioid use disorder in a patient in need thereof, wherein the patient has been identified and/or selected as having opioid use disorder , in an amount that is effective in treating the opioid use disorder and that does not increase end tidal CO2 in the patient.
In some embodiments provided herein is the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating opioid use disorder in a patient in need thereof, wherein a first end tidal CO2 is determined in the patient prior to administration of the medicament and a second first end tidal CO2 is determined in the patient after administration of the medicament, in an amount that is effective in treating the opioid use disorder, wherein the second end tidal CO2 is not higher than the first end tidal CO2.
In some embodiments provided herein is a use of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating opioid use disorder in a patient in need thereof, wherein the patient has been identified and/or selected as having opioid use disorder, wherein a first end tidal CO2 is determined in the patient prior to administration of the medicament and a second first end tidal CO2 is determined in the patient after administration of the medicament, in an amount that is effective in treating the opioid use disorder, wherein the second end tidal CO2 is not higher than the first end tidal CO2.
In some embodiments provided herein is a use of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating opioid use disorder in a patient in need thereof, wherein a first respiratory rate is determined in the patient
prior to administration of the medicament and a second respiratory rate is determined in the patient after administration of the medicament, in an amount that is effective in treating the opioid use disorder, wherein the second respiratory rate is not lower than the first respiratory rate.
In some embodiments provided herein is the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating opioid use disorder in a patient in need thereof, wherein the patient has been identified and/or selected as having opioid use disorder, wherein a first respiratory rate is determined in the patient prior to administration of the medicament and a second respiratory rate is determined in the patient after administration of the medicament, in an amount that is effective in treating the opioid use disorder; wherein the second respiratory rate is not lower than the first respiratory rate.
The severity of opioid use disorder may be determined, for example, by measuring the value of a clinical score associated with the opioid use disorder. Similarly, in some embodiments, the effectiveness of the treatment of opioid use disorder may be determined, for example, by measuring the value of a clinical score associated with the opioid use disorder following the treatment. Accordingly, in some embodiments, a method of treatment disclosed herein comprises determining the value for the patient of a clinical score associated with the opioid use disorder. In some embodiments, the method comprises determining that the value of the clinical score at a time point following administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof, is different from the value of the clinical score prior to or at the time of administration.
In some embodiments, the severity of the clinical score is determined by one or more criteria defined in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (also known as DSM-5), incorporated herein in its entirety. In some embodiments, the severity of the clinical score is determined in accordance with the patient global impression severity scale (also known as PGIS), incorporated herein in its entirety. In some embodiments, the severity of the clinical score is determined in accordance with the clinician global impression severity scale (also known as CGIS), incorporated herein in its entirety.
The effect of treatment with the compound of formula (I), or a pharmaceutically acceptable salt thereof, may be determined, for example, by measuring the reduction in the severity of a symptom of the opioid use disorder. Thus, in some embodiments, provided herein are methods as disclosed
herein, wherein the method reduces the severity of a symptom of the opioid use disorder by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35% or at least 40%. Thus, in some embodiments, provided herein are methods as disclosed herein, wherein the decrease in respiratory rate following administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof, is reduced by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35% or at least 40% relative to the decrease in respiratory rate prior to administration.
In some embodiments provided herein is a compound of Formula (I) or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, for use in treatment of a patient with alcohol use disorder. In some embodiments the compound of Formula (I) or pharmaceutically acceptable salt thereof, or the pharmaceutical composition, is administered to the patient orally. In some embodiments, the compound of Formula (I) or pharmaceutically acceptable salt thereof, or the pharmaceutical composition, is administered to the patient in an amount from about 6.25 mg to about 50 mg per day. In some embodiments the compound of Formula (I) or pharmaceutically acceptable salt thereof, or the pharmaceutical composition, is administered to the patient orally in an amount from about 6.25 mg to about 50 mg per day, such as about 12.5 mg per day to about 37.5 mg per day, such as about 25 mg per day. In some embodiments the compound of Formula (I) or pharmaceutically acceptable salt thereof, or the pharmaceutical composition, is administered to the patient orally in an amount from about 6.25 mg to about 50 mg per day, such as about 12.5 mg per day to about 37.5 mg per day, such as about 25 mg per day. In some embodiments, the compound of Formula (I) or pharmaceutically acceptable salt thereof is administered in an amount equal to about 5 mg to about 100 mg per day, such as about 5 mg per day, about 10 mg per day, about 15 mg per day, about 20 mg per day, about 25 mg per day, about 30 mg per day, about 35 mg per day, about 40 mg per day, or about 50 mg per day. In some embodiments, the compound of Formula (I) or pharmaceutically acceptable salt thereof is administered orally in an amount equal to about 5 mg to about 100 mg per day, such as about 5 mg per day, about 10 mg per day, about 15 mg per day, about 20 mg per day, about 25 mg per day, about 30 mg per day, about 35 mg per day, about 40 mg per day, or about 50 mg per day.
In some embodiments provided herein is the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating alcohol use disorder in a patient in need
thereof, the methods comprising administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the alcohol use disorder and that does not cause respiratory depression in the patient.
In some embodiments provided herein is the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having alcohol use disorder; and ii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the alcohol use disorder and that does not cause respiratory depression in the patient.
In some embodiments provided herein is the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. determining a first respiratory status in the patient; ii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the alcohol use disorder; and iii. determining a second respiratory status in the patient; wherein the second respiratory status is not lower than the first respiratory status.
In some embodiments provided herein is the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having or susceptible to alcohol use disorder; ii. determining a first respiratory status in the patient; iii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the alcohol use disorder; and iv. determining a second respiratory status in the patient; wherein the second respiratory status is not lower than the first respiratory status.
In some embodiments provided herein is the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating alcohol use disorder in a patient in need thereof, the methods comprising administering to the patient the compound or a pharmaceutically
acceptable salt thereof in an amount that is effective in treating the alcohol use disorder and that does not decrease blood oxygen saturation in the patient.
In some embodiments provided herein is the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having alcohol use disorder; and ii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the alcohol use disorder and that does not decrease blood oxygen saturation in the patient.
In some embodiments provided herein is the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. determining a first blood oxygen saturation in the patient; ii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the alcohol use disorder; and iii. determining a second blood oxygen saturation in the patient; wherein the second blood oxygen saturation is not lower than the first blood oxygen saturation.
In some embodiments provided herein is the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having alcohol use disorder; ii. determining a first blood oxygen saturation in the patient; iii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the alcohol use disorder; and iv. determining a second blood oxygen saturation in the patient; wherein the second blood oxygen saturation is not lower than the first blood oxygen saturation.
In some embodiments provided herein is the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating alcohol use disorder in a patient in need
thereof, the methods comprising administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the alcohol use disorder and that does not increase end tidal CO2 in the patient.
In some embodiments provided herein is the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having alcohol use disorder; and ii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the alcohol use disorder and that does not increase end tidal CO2 in the patient.
In some embodiments provided herein is the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. determining a first end tidal CO2 in the patient; ii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the alcohol use disorder; and iii. determining a second end tidal CO2 in the patient; wherein the second end tidal CO2 is not higher than the first end tidal CO2.
In some embodiments provided herein is the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having alcohol use disorder; ii. determining a first end tidal CO2 in the patient; iii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the alcohol use disorder; and iv. determining a second end tidal CO2 in the patient; wherein the second end tidal CO2 is not higher than the first end tidal CO2.
In some embodiments provided herein is the compound of Formula (I), or a pharmaceutically
acceptable salt thereof, for use in a method of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. determining a first respiratory rate in the patient; ii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the alcohol use disorder; and iii. determining a second respiratory rate in the patient; wherein the second respiratory rate is not lower than the first respiratory rate.
In some embodiments provided herein is the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating alcohol use disorder in a patient in need thereof, the methods comprising: i. identifying and/or selecting a patient having alcohol use disorder; ii. determining a first respiratory rate in the patient; iii. administering to the patient the compound or a pharmaceutically acceptable salt thereof in an amount that is effective in treating the alcohol use disorder; and iv. determining a second respiratory rate in the patient; wherein the second respiratory rate is not lower than the first respiratory rate.
In some embodiments provided herein is a use of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating alcohol use disorder in a patient in need thereof, in an amount that is effective in treating the alcohol use disorder and that does not cause respiratory depression in the patient.
In some embodiments provided herein is a use of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating alcohol use disorder in a patient in need thereof, wherein the patient has been identified and/or selected as having alcohol use disorder, in an amount that is effective in treating the alcohol use disorder and that does not cause respiratory depression in the patient.
In some embodiments provided herein is a use of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating alcohol use disorder in a patient in need thereof, wherein a first respiratory status is determined in the patient prior to administration of the medicament and a second respiratory status is
determined in the patient after administration of the medicament, in an amount that is effective in treating the alcohol use disorder, wherein the second respiratory status is not lower than the first respiratory status.
In some embodiments provided herein is a use of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating alcohol use disorder in a patient in need thereof, wherein the patient has been identified and/or selected as having alcohol use disorder, wherein a first respiratory status is determined in the patient prior to administration of the medicament and a second respiratory status is determined in the patient after administration of the medicament, in an amount that is effective in treating the alcohol use disorder, wherein the second respiratory status is not lower than the first respiratory status.
In some embodiments provided herein is a use of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating alcohol use disorder in a patient in need thereof, in an amount that is effective in treating the alcohol use disorder and that does not decrease blood oxygen saturation in the patient.
In some embodiments provided herein is a use of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating alcohol use disorder in a patient in need thereof, wherein the patient has been identified and/or selected as having alcohol use disorder, in an amount that is effective in treating the alcohol use disorder and that does not decrease blood oxygen saturation in the patient.
In some embodiments provided herein is a use of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating alcohol use disorder in a patient in need thereof, wherein a first blood oxygen saturation is determined in the patient prior to administration of the medicament and a second blood oxygen saturation is determined in the patient after administration of the medicament, in an amount that is effective in treating the alcohol use disorder, wherein the second blood oxygen saturation is not lower than the first blood oxygen saturation.
In some embodiments provided herein is a use of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating
alcohol use disorder in a patient in need thereof, wherein the patient has been identified and/or selected as having alcohol use disorder, wherein a first blood oxygen saturation is determined in the patient prior to administration of the medicament and a second blood oxygen saturation is determined in the patient after administration of the medicament, in an amount that is effective in treating the alcohol use disorder; wherein the second blood oxygen saturation is not lower than the first blood oxygen saturation.
In some embodiments provided herein is a use of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating alcohol use disorder in a patient in need thereof, in an amount that is effective in treating the alcohol use disorder and that does not increase end tidal CO2 in the patient.
In some embodiments provided herein is a use of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating alcohol use disorder in a patient in need thereof, wherein the patient has been identified and/or selected as having alcohol use disorder, in an amount that is effective in treating the alcohol use disorder and that does not increase end tidal CO2 in the patient.
In some embodiments provided herein is the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating alcohol use disorder in a patient in need thereof, wherein a first end tidal CO2 is determined in the patient prior to administration of the medicament and a second first end tidal CO2 is determined in the patient after administration of the medicament, in an amount that is effective in treating the alcohol use disorder, wherein the second end tidal CO2 is not higher than the first end tidal CO2.
In some embodiments provided herein is a use of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating alcohol use disorder in a patient in need thereof, wherein the patient has been identified and/or selected as having alcohol use disorder, wherein a first end tidal CO2 is determined in the patient prior to administration of the medicament and a second first end tidal CO2 is determined in the patient after administration of the medicament, in an amount that is effective in treating the alcohol use disorder, wherein the second end tidal CO2 is not higher than the first end tidal CO2.
In some embodiments provided herein is a use of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating alcohol use disorder in a patient in need thereof, wherein a first respiratory rate is determined in the patient prior to administration of the medicament and a second respiratory rate is determined in the patient after administration of the medicament, in an amount that is effective in treating the alcohol use disorder, wherein the second respiratory rate is not lower than the first respiratory rate.
In some embodiments provided herein is the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating alcohol use disorder in a patient in need thereof, wherein the patient has been identified and/or selected as having alcohol use disorder, wherein a first respiratory rate is determined in the patient prior to administration of the medicament and a second respiratory rate is determined in the patient after administration of the medicament, in an amount that is effective in treating the alcohol use disorder; wherein the second respiratory rate is not lower than the first respiratory rate.
The severity of alcohol use disorder may be determined, for example, by measuring the value of a clinical score associated with the alcohol use disorder. Similarly, in some embodiments, the effectiveness of the treatment of alcohol use disorder may be determined, for example, by measuring the value of a clinical score associated with the alcohol use disorder following the treatment. Accordingly, in some embodiments, a method of treatment disclosed herein comprises determining the value for the patient of a clinical score associated with the alcohol use disorder. In some embodiments, the method comprises determining that the value of the clinical score at a time point following administration of the compound of Formula (I) is different from the value of the clinical score prior to or at the time of administration.
In some embodiments, the severity of the clinical score is determined by one or more criteria defined in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (also known as DSM-5), incorporated herein in its entirety. In some embodiments, the severity of the clinical score is determined in accordance with the patient global impression severity scale (also known as PGIS), incorporated herein in its entirety. In some embodiments, the severity of the clinical score is determined in accordance with the clinician global impression severity scale (also known as CGIS), incorporated herein in its entirety.
The effect of treatment with the compound of formula (I) may be determined, for example, by measuring the reduction in the severity of a symptom of the alcohol use disorder. Thus, in some embodiments, provided herein are methods as disclosed herein, wherein the method reduces the severity of a symptom of the alcohol use disorder by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35% or at least 40%. Thus, in some embodiments, provided herein are methods as disclosed herein, wherein the decrease in respiratory rate following administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof, is reduced by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35% or at least 40% relative to the decrease in respiratory rate prior to administration.
Example 1
The potential additive effect of the compound of Formula (I) on the morphine-induced pharmacodynamic effects on the respiratory system was investigated based on the coadministration of morphine and the compound of Formula (I) in male cynomolgus monkeys (4-6 years old) under conscious and non-restrained conditions. Respiratory rate, tidal volume and minute volume were evaluated as the respiratory parameters. Oral and subcutaneous administrations were adopted for the compound of Formula (I) and morphine, respectively. Groups of male monkeys each consisted of 2 to 3 individuals were used.
When the monkeys were treated with morphine alone (morphine and vehicle), obvious decrease was observed in tidal volume and minutes volume compared to control group. While the decrease was sporadic at 3 mg/kg, it was persistent at 10 mg/kg. No apparent decrease was observed in respiratory rate, although sporadic increase was observed at 10 mg. These results suggested that morphine at 3 and 10 mg/kg induced suppression of the respiratory function.
When the monkeys were concomitantly treated with morphine (3 mg/kg) and the compound of Formula (I) (3 or 10 mg/kg), no remarkable difference was noted in the respiratory rate, tidal volume, or minute volume between the morphine/the compound of Formula (I) co-treated group (3 mg/kg morphine / 3 or 10 mg/kg of the compound of Formula (I)) and the corresponding morphine alone group (3 mg/kg morphine / vehicle). Also no remarkable difference was noted in the respiratory rate, tidal volume, or minute volume between the 10 mg/kg morphine / 3 or 10 mg/kg the compound of Formula (I) group and the 10 mg/kg morphine / vehicle group. From
the above results, the compound of Formula (I) at 3 and 10 mg/kg was not considered to potentiate respiratory suppression induced by morphine in cynomolgus monkeys.
MATERIALS AND METHODS
Test Article 1
- Name
Compound of Formula (I), also referred to as ASP8062.
- Amount
1.2 g
Vehicle (for administration of the compound of Formula (I))
- Name
0.5 w/v% methylcellulose solution (abbreviation: 0.5% MC)
- Amount
15 g
Test Article 2
- Name
Morphine hydrochloride injection 10 mg (10 mg/lmL)
Morphine hydrochloride injection 50 mg (50 mg/5mL)
Test System
- Species
Cynomolgus monkey (Seven male animals - 4 to 6 years old at receipt and at the first administration)
- Body Weight Range
4.1 to 5.6 kg
- Quarantine and Acclimatization
1. At the time of receipt, species, age, number of animals and gender were confirmed.
2. The acclimatization period was from the day of animal receipt to the day before the first administration.
3. The animals receipted have been quarantined and acclimatized at the test facility until they were transferred to this study.
4. The general condition was observed once a day throughout the acclimatization period.
- Number of Animals per Cage
One animal per cage.
Administration
- Administration Route
Compound of Formula (I) and its vehicle (0.5% MC suspension): Oral administration. Morphine and water for injection: Subcutaneous administration.
At each experiment day of administration, a single administration was adopted for the compound of Formula (I), morphine or the concomitant treatment of the compound of Formula (I) and morphine.
- Administration Method
Compound of Formula (I) and vehicle: After fasting for at least 16 h, forced gastric administration was performed between 9:00 and 11 :00 using a disposal syringe equipped with a catheter. Upon sampling of the test article for administration, it was stirred to become homogeneous. After completion of administration, the syringe was flushed with air at 10 mL (Animal No. 1, 2 and 3 were acclimated to oral dosing with a catheter at least twice prior to the first dosing, but it was not performed for the animal No. 4, 5, 6 and 7.).
Morphine and water for injection: After fasted for at least 16 h, subcutaneous administration at the back was performed between 9:00 and 11 :00 using a syringe equipped with a needle. For concomitant treatment with morphine, the compound of Formula (I) or vehicle was administered immediately after injection of morphine. In No. 3, since no inhibitory effect of morphine at 10 mg/kg was observed on respiratory function, No. 4, 5, 6 and No. 7 were additionally received and were administered morphine at 10 mg/kg for selection of that exhibiting inhibitory effect of morphine on respiratory function. As a result, No. 4 was selected. As for the No. 4, the respiratory rate increased and the tidal volume decreased 8 h after the concomitant treatment of 10 mg/kg morphine and the compound of Formula (I) 10 mg/kg, and these changes were also observed 24 h after the concomitant treatment. The respiratory function of No. 4 was measured for confirmation and the respiratory rate was higher than that of the predose value of the concomitant treatment of 10 mg/kg morphine and 10 mg/kg of the compound of Formula (I). Therefore, the 9th administration was not performed for No. 4. Moreover, since the respiratory rate remained high, it was not used and the evaluation was performed with No. 1 and 2 from the 9th administration.
The dosing volume was calculated based on body weights measured on the day before administration (for measurement of respiratory function) or the day of administration (for TK blood sampling) and the dosing value was rounded to the nearest minimum scale value of the syringe from the first decimal place. The dosing volumes of morphine and water for injection were rounded up to the minimum scale of the syringe from the second decimal place.
Preparation Method of the compound of Formula (I) Dosing Formulation
1. A required amount of the compound of Formula (I) was weighed and was ground with an agate mortar and pestle.
2. An appropriate amount of 0.5% MC was gradually added and mixed with a pestle and mortar to make a suspension. After the suspension was confirmed to be sufficiently homogeneous, it was transferred to a measuring cylinder.
3. The pestle and mortar was washed with 0.5% MC and the rinsing solution was transferred into the measuring cylinder.
4. The suspension was measured up to the target concentration by addition of 0.5%MC and then mixed by inversion.
5. The prepared dosing formulations were placed in brown glass vessels with a stir bar.
6. The prepared dosing formulations of the test article were stored under refrigeration (Actual range: 4.2°C to 7.1 °C; acceptable range: 1°C to 15°C) and protected from light, and used within 7 days after preparation.
Preparation of Morphine Dosing Solution
1. The stock solution was used as is.
2. A required amount of the stock solution of morphine was taken and placed into a graduated cylinder when it was necessary to dilute.
3. Water for injection was added to the desired concentration and mixed upside down.
4. The prepared solution was transferred to a glass container.
The Study Design and the Administration Schedule were as shown below:
Experimental Method
Apparatus for Measuring Respiratory Function
4CH Bias flow box No model, GM Company Ltd.
WBP chamber: No model, LSI Medience Corporation
Flow sensor used for WBP: TRD5715, Buxco Electronics, Inc.
Preamplifier module: MAX2275, Buxco Electronics, Inc.
Temperature-humidity probe used for WBP TRD5716, Buxco Electronics, Inc.
Data acquisition and analysis software: FinePointe software (Version 2.3.1.9), Data Sciences International, Inc.
Respiratory Function Measurement Method
1. The respiratory parameters were measured with whole body plethysmograph using a respiratory plethysmograph chamber.
2. Prior to dosing, animals were housed and acclimatized for more than 16 h.
3. The respiratory parameters were measured from 2 h or more before administration to 8 h 15 min or more after administration. For 24 h after administration, measurements were performed at about 15 min before and after the evaluation time point.
Evaluation Time Points
Pre-administration, 1, 2, 4, 8 and 24 h after administration
The time immediately after administration of the compound of Formula (I) and vehicle was taken as 0 min.
Evaluation Items
Respiratory function (respiratory rate, tidal volume and minute volume)
Data Processing and Data Handling
When it became difficult to acquire data due to body movements confirmed at the evaluation time points, data was acquired by analyzing the raw data which was acquired at the nearest to the evaluation time point (evaluation time point ±15 min). Each of the evaluation items was rounded to integers.
Respiratory Parameters
The mean values for 1 min before each of the evaluation time points (1 min from 59 to 60 min after administration for the evaluation time point of 60 min after administration) were taken as the measurement data.
Statistical Analysis
Items for Analysis
Respiratory Function (respiratory rate, tidal volume and minute volume)
Data
1. Data of each group was expressed as mean ± standard deviation (SD). In addition, the data for the group of 2 cases was expressed as the mean only.
2. Mean ± SD was expressed as integers by rounding off at the first decimal place.
3. Mean ± SD was calculated using Microsoft Excel 2010 (Microsoft Corporation Redmond, WA, USA).
Blood Sampling Time Points
3rd time administration (3 mg/kg of the compound of Formula (I)): 1, 2, 4, 8, and 24 h postdose
10th time administration (10 mg/kg of the compound of Formula (I)): pre-dose, 1, 2, 4, 8, and 24 h post-dose
Blood Sampling and Processing
Approximately 0.3 to 0.6 mL of blood was collected from the cephalic vein with a syringe containing heparin sodium and immediately cooled on ice and centrifuged (1830 / g, 10 min, 4°C) to obtain plasma of 0.1 to 0.3 mL or more. The obtained plasma (TK measurement sample) was stored in an ultra-low temperature freezer (acceptable range: -90 to -65°C) until shipping. A label indicating the study number, animal number, substance name, and dose was attached to each container of the TK measurement sample. The blood collected from the control group was discarded.
RESULTS AND DISCUSSION
In the 3 mg/kg morphine alone group (group 2: treatment with morphine and vehicle [0.5% MC]), the respiratory rate in the animal No. 2 was higher than that in the control group (group 1 : treatment with morphine vehicle [water for injection] and vehicle for the compound of Formula (I)) at 8 h after administration. In the 10 mg/kg morphine alone group (group 3), the respiratory rate in the animal No. 1 was higher than that in the control group at 4 h after administration.
As for the tidal volume, it was lower in the 3 mg/kg morphine alone group than that in the control group at 4 h (animal No. 1) and at 8 h (animal No. 2) after administration. The tidal volume in the 10 mg/kg morphine alone group was lower than that in the control group at 1 to 8 h (animal No. 1), 1, 2 and 8 h (animal No. 2) and 4 h (animal No. 4) after administration. As for the minute volume, it was lower in the 3 mg/kg morphine alone group than that in the control group at 4 h after administration (animal No. 1). The minute volume of 10 mg/kg morphine alone group was lower than that in the control group at 1, 2 and 8 h (animal No. 1), 2 and 24 h (animal No. 2) and 1 to 4 h (animal No. 4) after administration. Although the minute volume of animal No. 2 in 10 mg/kg morphine alone group was lower than that in the control group at 24 h after administration, it was at the similar level at 8 h after administration as that in the predose value. Therefore, the lower value of the minute volume of animal No. 2 at 24 h was considered to be a transient change but not related to the inhibitory effect of morphine on respiratory function.
The increases in respiratory rate in morphine 3 mg/kg (animal No. 2) and 10 mg/kg (animal
No. 1) alone groups were considered to be a compensatory change accompanying to the decrease in tidal volume. As for the low value of tidal volume observed at 8 h after administration in the morphine 3 mg/kg (animal No. 2) or 10 mg/kg (animal No. 1 and 2) alone groups, it was inferred to be a change not related to the administration of morphine considering the un-change of the minute volume and general changes of plasma morphine concentration.
From the above results, it was confirmed that administration of morphine 3 and 10 mg/kg induced suppression of the respiratory function in a dose-related manner as the action time. Next, coadministrations of the compound of Formula (I) at 3 or 10 mg/kg, and morphine 3 or 10 mg/kg were performed. In the coadministration of 3 mg/kg morphine and 3 mg/kg of the compound of Formula (I) (group 7), the tidal volume in the animal No. 1 was lower at 2 and 8 h after administration than that of the predose value. As for the low value of tidal volume observed at 8 h after administration, it was inferred to be a meaningless change considering the un-change of the minute volume and the changes of plasma morphine concentration. With regard to the low value of tidal volume and minute volume at 2 h after administration and a higher value of minute volume at 4 h after administration in the animal No.1 when compared with the pre-dose value, these changes were not considered to be related to the administration of the compound of Formula (I) because no change was noted at 2 or 4 h after administration in the coadministration of 3 mg/kg morphine and 10 mg/kg of the compound of Formula (I). No clear difference in respiratory rate, tidal volume or minute volume was observed in the coadministration of 3 mg/kg morphine and 3 mg/kg of the compound of Formula (I) compared to that in the 3 mg/kg morphine alone group.
In the coadministration of 3 mg/kg morphine and 10 mg/kg of the compound of Formula (I) (group 6), tidal volume and minute volume in the animal No. 1 was lower at 4 and 8 h after administration than that of the pre-dose value. However, no clear difference in respiratory rate, tidal volume or minute volume was observed compared to that in the 3 mg/kg morphine alone group.
In the coadministration of 10 mg/kg morphine and 3 mg/kg of the compound of Formula (I) (group 5), tidal volume in the animal No. 1 and 2 was lower at 4 and 8 h after administration than those of the predose values. Minute volume in the animal No. 1 was lower at 1 and 8 h after administration than that of the pre-dose value. However, no clear difference in respiratory
rate, tidal volume or minute volume was observed compared to that in the 10 mg/kg morphine group.
In the coadministration of 10 mg/kg morphine and 10 mg/kg of the compound of Formula (I) (group 4), respiratory rate in the animal No. 4 was lower from 1 to 4 h after administration and was higher at 8 and 24 h after administration than that of the pre-dose value. With regard to tidal volume, a lower value was noted at 2 to 24 h after administration than that of the pre-dose value in the animal No. 1, a lower value was noted at 1, 2 and 8 h after administration than that of the pre-dose value in the animal No. 2, and a higher value at 1 to 4 h after administration and a lower value at 8 and 24 h after administration than that of the pre-dose value in the animal No. 4. As for the minute volume, a lower value at 1, 2, 4 and 24 h after administration in the animal No. 1, a lower value at 2 and 8 h after administration in the animal No. 2, and a lower value at 1, 2, 4 and 8 h after administration in the animal No. 4 were noted compared to the pre-dose values. However, no clear difference in respiratory rate, tidal volume or minute volume in the animal No.1 and 2 was observed compared to that in the 10 mg/kg morphine control group. As for No. 4, reactions similar to those of the 10 mg/kg morphine alone group were noted up to 4 h after administration, the respiratory rate increased at 8 h after administration while there was a decrease in minute volume. These changes were also noted at 24 h after administration, and the respiratory rate remained high even 19 days after administration. Since none of these reactions were noted in other animals and there were no changes in behavior or general condition associated with increased respiratory rate in the video recordings, the cause of these reactions remains unknown but considered to be specific to this individual.
From the above results, as no remarkable difference was noted in the respiratory rate, tidal volume, or minute volume following administration of the compound of Formula (I) at 3 or 10 mg/kg under the influence of morphine (respiratory depression) at 3 or 10 mg/kg compared to those of morphine and vehicle administration, the compound of Formula (I) at 3 and 10 mg/kg was not considered to potentiate respiratory depression induced by morphine.
Table 1 Respiratory parameters (Respiratory rate)
Vehicle: 0.5% MC
B.A. : Before adtesistration
* : The value represents the mean value of the date of the animal No. 1 and 2.
Vehicle: 0 5% MC
B.A.: Before administration
*: The value represents the mean value of she data of the animal No. 1 and 2.
Vehicle: 0 5% MC
B.A : Before administration
*: The value represents; the mean value of the data of the animal No. 1 and 2
The results of the PK analysis are shown below:
Plasma concentrations of ASP8062 were measured by LC-MS/MS with the following calibration curve ranges Study SNBL.-PKMs-190042 was the calibration curve range of (0.12 to 1200 ug/mL and Study SNBL-PKMs-190074 was the calibration curve runge of 0.1 m
1000 gg/ml... Pharmacokinetic parameters were calculated using the noncompartmental analysis model of Phoenix WinNonlin.
RESULTS
Example 2
Effect of ASP8062 on morphine self-administration and morphine-induced respiratory suppression in monkeys
A self-administration method was used to investigate the potential of ASP8062 for suppressing the reinforcing effects of morphine. Three rhesus monkeys were pretreated with ASP8062 (0.3, 1 or 3 mg/kg) by oral administration 1 h prior to a 2-h morphine self-administration session (0.03 mg/kg, iv, per injection) under a fixed-ratio 5 schedule. The potential worsening of morphine-induced respiratory suppression by ASP8062 after coadministration of morphine (10 mg/kg, sc) and ASP8062 (10 mg/kg, po) was examined in cynomolgus monkeys using a custom-made whole-body plethysmograph. Plasma concentrations of ASP8062 (3 or 10 mg/kg,
po) were assessed in cynomolgus monkeys using liquid chromatography -tandem mass spectroscopy (LC-MS/MS).
Results: ASP8062 dose-dependently decreased the number of morphine self-administrations, with significant differences from the vehicle-treated group observed at 3 mg/kg in all animals tested. Exposure levels at 3 mg/kg observed in monkeys were comparable to the clinical exposure levels which positive pharmacodynamic effects were previously shown. Further, ASP8062 did not potentiate morphine-induced respiratory suppression up to exposure levels higher than the clinically relevant dose.
Conclusions: A clinically relevant dose of ASP8062 is expected to reduce opioid use in OUD patients without inducing respiratory suppression.
1. Materials and methods
1.1. Morphine self-administration study
1.1.1. Animals
Three adult rhesus monkeys (1 male, 2 female) were purchased from Shin Nippon Biomedical Laboratories (SNBL) Ltd., (Tokyo, Japan). The monkeys weighing between 4.16 and 6.14 kg had been trained in self-administrations and used in a series of self-administration studies. The monkeys were housed individually at 22-28°C, 40-80% humidity, and under a 12-hour light/dark cycle (lights on at 7:00 a.m.). The monkeys received approximately 120 g of solid feed (PS-A, Oriental Yeast Co., Ltd., Chiba, Japan) once a day. Additionally, half a banana was given to each monkey at least 4 times weekly. The monkeys were allowed free access to drinking water. These animals were restrained in individual stainless cages (75W x 90D x 100H cm) by metal harnesses and free-jointed metal arms in a monkey room. All experiments were conducted in accordance with the principles specified by the Institutional Animal Care and Use Committee of Ina Research Inc. (Ina, Japan).
1.1.2. Drugs
Morphine hydrochloride hydrate, JP was purchased from Takeda Pharmaceutical Company Limited (Tokyo, Japan). ASP8062 was provided by Astellas Pharm Inc. (Tsukuba, Japan).
1.1.3. Surgery
Each animal was implanted with a silicon catheter (outer diameter: 3 mm; inner diameter: 1 mm) into the jugular or femoral vein under pentobarbital anesthesia connected to an automatic drug infusion apparatus. Additionally, an indwelling silicon catheter was placed in the stomach. The end of the catheter was exited from the dorsal region (between the scapulae), connected to a sterile disposable 18G blunt needle and placed under the dorsal harness.
1.1.4. Apparatus
For the self-administration experiments, the experiment was conducted in the home cage fitted with one response lever and one red light approximately 5 cm above the lever. A predetermined volume of dosing solution or saline was automatically infused through the catheter when the monkey pressed the lever. Scheduling of infusions and collection of data were controlled by a personal computer system (MED-PC, Med Associates Inc., VT, USA) (Fujiwara et al., 2016).
1.1.5. Drug self-administration procedure
The animals were observed for five trials of self-administration sessions as detailed below.
Each session was held for 2 h per day, during which time animals received the dosing formulation under the condition that they press the lever 5 times (fixed ratio of 5: FR5). A one- minute time-out followed each self-administration. Lever pressing during the time-out period was regarded as invalid. Each trial was started on a Monday.
Trial 1 : On the first day, the animals were allowed to self-administer morphine (0.03 mg/kg/infusion) without limitations on the number of self-administrations/day; the number of administrations was >11 times for all monkeys. Subsequently, self-administration with saline was trialed on 1 day. Finally, the animals were subjected to self-administration with morphine for 3 days following pretreatment with vehicle, without limitations on the number of self- admini strati ons/ day .
Trial 2: On the first day, the animals were allowed to self-administer morphine (0.03 mg/kg/infusion) without limitations on the number of self-administrations/day; the number of administrations was >11 times and not markedly different from the mean number of selfadministrations in the first trial (within approximately 1/2 or 2-fold of the mean). Subsequently, self-administration with saline was trialed on 1 day. Finally, the animals were subjected to selfadministration with saline (0.25 mL/kg/infusion) for 3 days following pretreatment with vehicle, without limitations on the number of self-administrations/day.
Trial 3-5: On the first day, the animals were allowed to self-administer morphine (0.03 mg/kg/infusion) without limitations on the number of self-administrations/day; the number of administrations was >11 times and not markedly different from the mean number of selfadministrations in the first trial (within approximately 1/2 or 2-fold of the mean). Subsequently, self-administration with saline was trialed on 1 day. Finally, the animals were subjected to selfadministration with morphine (0.03 mg/kg/infusion) for 3 days following pretreatment with ASP8062 (0.3, 1, or 3 mg/kg/ig infusion), without limitations on the number of self- admini strati ons/ day .
1.1.6. Stati sti cal analy si s
Mean and standard error of the daily number of self-administrations on the last 3 days were calculated for each trial. The number of self-administrations was compared between morphine and the negative control group using Student’s t-test. The number of self-administrations was compared between the morphine group and ASP8062 group using William’s multiple comparisons test. P < 0.05 was considered statistically significant.
1.2. Measurement of respiratory function and pharmacokinetics study
1.2.1. Animals
Four male cynomolgus monkeys were purchased from Hamri Co., Ltd. (Koga, Japan). The animals were approximately 4 to 6 years old and weighed approximately 4.1 to 5.3 kg throughout the study period. The animals were housed individually in stainless steel cages (width: 718 x depth: 648 x height: 778 mm) which met the conditions for housing monkeys. All experiments were conducted in accordance with the principles specified by the Institutional Animal Care and Use Committee of LSI Medience Co. (Kumamoto, Japan).
1.2.2. Drugs
Morphine hydrochloride injection 10 mg (10 mg/1 mL) and 50 mg (50 mg/5 mL) were purchased from Takeda Pharmaceutical Company Limited (Tokyo, Japan). ASP8062 was provided by Astellas Pharm Inc. (Tsukuba, Japan).
1.2.3. Apparatus
A custom-made whole-body plethysmograph system for measuring respiratory function in
unrestrained monkeys was used. The system consisted of the following components: 4CH Bias flow box (GM Company Ltd.); Whole body plethysmography (WBP) chamber (LSI Medience Co.); flow sensor for WBP (TRD5715, Buxco Electronics, Inc.); preamplifier module (MAX2275, Buxco Electronics, Inc.); and temperature-humidity probe for WBP (TRD5716, Buxco Electronics, Inc.). FinePointe software (Version 2.3.1.9, Data Sciences International, Inc.) was used for data acquisition.
1.2.4. Respiratory responses to drugs
Respiratory parameters (respiratory rate, tidal volume and minute volume) were measured according to the method described by lizuka et al. (2010) using a respiratory plethysmograph chamber. Prior to dosing, 3 of the 4 animals were housed and acclimatized to the chamber for more than 16 h. The time immediately after oral administration of ASP8062 (10 mg/kg po) and vehicle was defined as 0 min. Evaluation time points were before administration and 1, 2, and 4 h after administration. Mean values measured for 1 min before each of the evaluation time points were defined as the measurement data.
1.2.5. Pharmacokinetic analysis
Approximately 0.3 to 0.6 mL of blood was collected from the cephalic vein with a syringe containing heparin sodium and immediately cooled on ice and centrifuged to obtain 0.1 to 0.3 mL or more of plasma. The obtained plasma was stored and sent to SNBL, Ltd (Wakayama, Japan). Plasma concentrations of ASP8062 (3 or 10 mg/kg, po) were measured using liquid chromatography -tandem mass spectroscopy (LC-MS/MS) at a calibration curve range of 0.12 to 1200 ng/mL or 0.1 to 1000 ng/mL at SNBL, Ltd. Pharmacokinetic parameters were calculated using the noncompartmental analysis model of Phoenix WinNonlin (Certara, NJ, USA).
1.2.6. Stati sti cal analy si s
Respiratory function parameters are reported as mean ± standard deviation (SD). For PK analysis, data from 3 mg/kg ASP8062 group are expressed as mean ± SD. In addition, data from the 10 mg/kg ASP8062 group comprising 2 cases are expressed as mean only. Data were calculated using Microsoft Excel 2010 (Microsoft Corporation Redmond, WA, USA).
2. Results
2.1. Effect of ASP8062 on morphine self-administration
ASP8062 significantly reduced the mean number of morphine self-administrations observed
across 3 days. The effect was dose-dependent and observed at all dose levels of ASP8062 in 1 of the 3 animals and at 3 mg/kg in the remaining 2 animals, compared to vehicle control (Fig. 1). No gross behavioral signs were observed in any animal during the self-administration period.
2.2. Effect of ASP8062 on respiratory systems
When treated with 10 mg/kg morphine alone (morphine and ASP8062 vehicle), the monkeys showed an obvious decrease in tidal volume and minute volume but not respiratory rate compared to the control group (Fig. 2-4). When concomitantly treated with 10 mg/kg morphine and 10 mg/kg ASP8062, no marked differences were observed in any respiratory parameters between the morphine alone group and ASP8062 co-treated group (Fig. 2-4).
2.3. Pharmacokinetic analysis
Plasma concentrations of ASP8062 after single oral administration to cynomolgus monkeys (no morphine infusion) are shown in Figure 5. The Cmax and AUC24 values were 202 ng/mL and 1700 ng h/mL at 3 mg/kg, and 404 ng/mL and 4660 ng h/mL at 10 mg/kg, respectively.
3. Discussion
Previous preclinical (Bexis et al., 2003; Saharei et al., 2009; Tsuji et al., 1996; Zarrindast and Mousa-Ahmadi, 1999) and clinical studies (Assadi et al., 2003) of baclofen have suggested that facilitating agonistic activity of the GAB AB receptor may be an attractive approach for treating OUT). Several studies have investigated the receptor’s mechanism of action (MoA) for reducing opioid use. A study by Yoon et al. (2007) demonstrated that pretreatment with baclofen dose- dependently reduced the rat morphine-maintenance response, an effect that was reversed following injection of GAB AB receptor antagonist SCH50911. Similarly, another study showed that inhibition of conditioned place preference in rats after microinjection of baclofen into the VTA was blocked by an intra- VTA microinjection of the GAB AB receptor antagonist 2- hydroxysaclofen (Xi and Stein, 1999). These results support the working hypothesis that GABAB-receptor activation inhibits a key pathway involved in reinforcing effects, namely, the midbrain dopaminergic pathway in which dopamine is release from the VTA (Fadda et al., 2003) causing a subsequent increase in dopamine levels in the nucleus accumbens (Spangel and Weiss, 1999).
In the present study, we found that the GAB AB receptor PAM, ASP8062, decreased morphine
self-administration after intragastric administration to rhesus monkeys. The GAB AB receptor is listed as the National Institute on Drug Abuse’s highest priority pharmacological target for the development of novel therapeutics for treating OUD (Rasmussen et al., 2019). Evidence has emerged indicating that PAMs can enhance the effects of GABA at GAB AB receptors and have therapeutic effects similar to agonists but with superior side-effect profiles (Filip et al., 2015). Nonhuman primates are more phylogenetically related to humans than any other species (Smith, 2020); similarly, their long lives and complex social systems most resemble those of humans. Further, the self-administration paradigm is a commonly recognized standard preclinical model for substance abuse. Thus, the morphine self-administration method using nonhuman primates adopted in the present study is thought to be reflective of substance abuse in humans. The positive findings along with support from the aforementioned MoA strongly suggest that ASP8062 has potential clinical efficacy for treating OUD.
CNS penetration and GABAergic pharmacodynamic activity, along with acceptable safety and tolerability were confirmed in phase 1 studies of ASP8062 (Walzer et al., 2020). Penetration of ASP8062 into the CNS is rapid, with nearly 50% of the plasma unbound drug reaching the cerebrospinal fluid (CSF) fraction (Walzer et al., 2020). A single dose of 35 mg or 70 mg ASP8062 resulted in a significant increase in slow-wave sleep and growth hormone release in healthy volunteers, suggesting that ASP8062 exerts GABAergic pharmacodynamic effects (Walzer et al., 2021). In the clinical pharmacodynamic study, Cmax and AUC24 values at 70 mg were 165 ng/mL and 1570 ng h/mL, respectively. These exposure levels are comparable to the values obtained in nonhuman primates in the present study (Cmax and AUC24 values were 202 ng/mL and 1700 ng h/mL, respectively, at 3 mg/kg), further supporting the drugs’ potential clinical efficacy in OUD.
Opioid-induced respiratory depression is a well-known side effect, and the possibility of exaggerating this effect with concomitant administration of ASP8062 is an important issue that requires addressing. Opioids depress respiration by activating opioid receptors expressed on neurons within the respiratory networks of the brainstem and outside the CNS (Algera et al., 2019). An off-target profiling study demonstrated that ASP8062 at 10 pM (40759 ng/mL) had no appreciable affinity for any of 55 receptors, channels, transporters and/or enzymes, including the human p-opioid receptor (Murai et al., 2019). lizuka et al. (2010) developed a custom-made whole-body plethysmograph for measuring respiratory function in unanesthetized and unrestrained nonhuman primates. We used this method to investigate the potential of ASP8062
for potentiating morphine-induced respiratory suppression in vivo. While administration of morphine (10 mg/kg s.c.) resulted in a sustained reduction in tidal volume and minute volume without changing respiratory rate, administration of ASP8062 at a supratherapeutic exposure level did not potentiate respiratory suppression (Cmax and AUC24 values were 404 ng/mL and 4660 ng h/mL, respectively, at 10 mg/kg). These results suggest that preclinically efficacious exposure levels of ASP8062 may be safely tested in a clinical study of OUD patients.
In conclusion, ASP8062 suppressed morphine self-administration in a non-human primate selfadministration model. Efficacious exposure levels in the preclinical model were comparable to those observed in the clinic with which acceptable safety and GABAergic pharmacodynamic effects have been confirmed. ASP8062 showed no preclinical signs of potentiating morphine- induced respiratory suppression at supratherapeutic exposure levels. These results suggest that ASP8062 may reduce opioid use in OUD patients without serious adverse events, and further development of ASP8062 as a potential treatment option for OUD is warranted.
Example 3
A Phase 1 Study to Assess Potential Interaction Between ASP8062 and Alcohol in Healthy Adult Subjects
ASP8062 is a novel orally active GAB AB receptor positive allosteric modulator in clinical development for the treatment of alcohol use disorder (AUD) and opioid use disorder (OUD). This study assessed the potential pharmacokinetic/pharmacodynamic interaction between ASP8062 and alcohol under single-dose conditions in healthy adults.
Methods:
A double-blind, placebo-controlled, crossover phase 1 study was conducted in which 20 subjects were randomly assigned to four treatment sequences (ASP8062 + alcohol; ASP8062 + placebo alcohol; placebo + alcohol; placebo + placebo alcohol) each consisting of four treatment periods, separated by washout periods of at least 14 days. An analysis of variance was used to assess pharmacokinetic interaction and a mixed effects analysis of covariance was used to assess pharmacodynamic interaction.
Results/Outcomes:
After administration of alcohol, a mild to minimal increase in plasma exposure (AUCinf and
Cmax) of ASP8062 was observed, but tmax and b/2 for ASP8062 remained unchanged after
administration of alcohol. In contrast, ASP8062 did not affect the AUCiast and Cmaxof ethanol. No clinically relevant differences in cognition measurements were observed with ASP8062 compared with placebo, but there were expected impairments in psychomotor and executive function with alcohol alone. ASP8062 in combination with alcohol resulted in worse scores in cognition measurements than alcohol alone, but this potentiation was not consistent. ASP8062 administered alone was safe and well-tolerated and safety findings in subjects administered alcohol alone were not augmented when ASP8062 was administered in combination with alcohol.
Conclusions/Interpretation:
The data support further clinical studies investigating ASP8062 in patients with AUD.
METHODS
Study design
This study in healthy adult subjects utilized a randomized, double-blind, placebo- controlled, four-period, crossover design to avoid evaluation bias with respect to safety and tolerability endpoints (NCT04003402). All enrolled subjects were randomized to one of four treatment sequences, and each treatment sequence consisted of four treatment periods separated by a washout period of at least 14 days. Subjects were screened for a maximum of 28 days prior to administration of investigational product on Day 1 of Period 1. Eligible subjects were admitted to the clinical unit one day before the four treatment periods (Day -1), each of which lasted for a total duration of 6 days and 5 nights. The four assigned treatments were: (A) ASP8062 + alcohol; (B) ASP8062 + placebo alcohol; (C): placebo + alcohol; (D): placebo + placebo alcohol. On Day 1 of each period, ASP8062 or placebo was administered as a single 60-mg oral dose under fasting conditions with 240-mL water. ASP8062 60 mg, in a newly developed ASP8062 30-mg tablet formulation, was chosen based on the results from a previously conducted relative bioavailability study and was expected to provide plasma ASP8062 exposures comparable to exposures in the previous clinical studies. The alcohol dose was 0.6-g ethanol/kg for female subjects and 0.7-g ethanol/kg for male subjects. The respective doses were selected as a dose of alcohol (equivalent to approximately 4 units for a 70-kg subject) known to cause a reliable, measurable, and consistent decrease in cognition.
One hour after receiving ASP8062 or placebo, alcohol or placebo alcohol was administered as a single oral dose within 10 minutes under the existing fasting conditions, after which subjects
had to remain awake in a semi -recumbent position and avoid lying on either the left or right side for 2 hours postdose. Only alcohol or placebo alcohol was allowed from at least 10 hours predose through 4 hours postdose. Subjects were discharged from the clinical unit on Day 5 of each period, on the condition that all required assessments had been performed and that there were no medical reasons for a longer stay in the clinical unit. Subjects returned to the clinical unit on Days 7 and 10 for pharmacokinetic blood sampling. The study was completed with an end-of-study visit, which took place between 5-9 days after Day 10 of Period 4 or at early discontinuation from the study.
This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, Good Clinical Practice, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines, and applicable laws and regulations. An institutional review board approved the written informed consent that was obtained from each subject prior to the initiation of any study-specific procedures. Subjects were also required to sign a Health Insurance Portability and Accountability Act authorization form. The study protocol and informed consent document were approved by Aspire IRB (Santee, CA), and the study was conducted at Parexel International - EPCU Baltimore (Baltimore, MD). Participants were compensated based on completion of study visits. Participants who dropped out or withdrew from the study received a prorated amount of compensation based on the scheduled portions of the study completed.
Study population
Healthy men and women, aged 21-55 years, with a body mass index between 18.5 and 32 kg/m2, who consumed alcohol regularly but did not meet the Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 criteria for alcohol use disorders, and were able to consume 3-4 standard drinks at one occasion without causing excessive intoxication (based on the discretion of the principal investigator), were eligible for inclusion in this study. Female subjects had to be of nonchildbearing potential and not breastfeeding for at least 3 months prior to screening, throughout the study period, and for 28 days after final administration of the investigational product. Male subjects and their female spouse/partners who were of childbearing potential were required to use contraception throughout the study period and for 90 days after final administration of the investigational product.
Subjects were excluded from the study if they had: a) any known or suspected hypersensitivity
to ASP8062 or alcohol; liver function tests (alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, and total bilirubin) >1.5x upper limit of normal (ULN) on Day -1 of Period 1; b) a clinically significant history of allergic conditions; c) a history or evidence of any clinically significant cardiovascular, gastrointestinal, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, renal and/or other major disease or malignancy, as judged by the investigator; d) an untreated moderate or severe mental illness; e) a relevant history of suicide attempt or suicidal behavior; f) smoked, used tobacco-containing products and nicotine or nicotine-containing products within 6 months prior to screening, or tested positive for cotinine at screening; g) a history of alcoholism or drug/ chemi cal/sub stance abuse within 2 years prior to screening, or tested positive for alcohol at screening or on Day -1; h) used any drugs of abuse (amphetamines, barbiturates, benzodiazepines, cannabinoids, ***e and/or opiates) within 3 months prior to Day -1, or the subject tested positive for drugs of abuse (amphetamines, barbiturates, benzodiazepines, cannabinoids, ***e and/or opiates) at screening or on Day -1 and/or used any inducer of metabolism (eg, barbiturates and rifampin) in the 3 months prior to Day -1.
Study endpoints
The primary objective was to assess the potential for pharmacokinetic and pharmacodynamic interaction between ASP8062 and alcohol. Primary pharmacokinetic endpoints for ASP8062 in plasma were area under the concentration-time curve (AUC) from the time of dosing extrapolated to time infinity (AUCinf) and maximum concentration (Cmax); AUC from the time of dosing to the last measurable concentration (AUCiast) and Cmax were the primary pharmacokinetic endpoints for plasma ethanol. Primary pharmacodynamic endpoints were comprised of the Cogstate battery and postural stability test. Assessments by Cogstate battery included the Detection test to measure psychomotor function, the Identification test to measure attention, the One-back test to measure working memory, and the Groton Maze Learning Test (GMLT) to measure executive function (Chen et al., 2015).
For the pharmacokinetic assessments of ASP8062, blood samples were collected on Day 1, predose (ASP8062/placebo ASP8062), and at the following postdose (ASP8062/placebo ASP8062) time points: 15 minutes, 30 minutes, 45 minutes, 60 minutes, 75 minutes, 90 minutes, 105 minutes, 2 hours, 2 hours 30 minutes, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 12 hours, 14 hours, 16 hours (Day 1), 24 hours (Day 2), 36 hours (Day 2), 48 hours
(Day 3), 72 hours (Day 4), 96 hours (Day 5), 144 hours (Day 7), and 216 hours (Day 10). In each time period, blood samples for pharmacokinetic assessments of alcohol were collected predose (ASP8062/placebo ASP8062) on Day 1 and at the following postdose (alcohol/placebo alcohol) time points on Day 1 : 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, and 7 hours. Plasma concentrations of ASP8062 and ethanol were determined using validated liquid chromatography -tandem mass spectrometry and gas chromatography with flame ionization detection methods, respectively.
Cogstate battery pharmacodynamic assessments were performed twice on Day -1 of Period 1 as practice assessments. The postural stability test assessed via the single-leg stance test was performed once on Day -1 of Period 1 as a practice assessment. All pharmacodynamic tests were repeated on Day 1 of each period, predose (ASP8062/placebo ASP8062), and then postdose (ASP8062/placebo ASP8062) at the following time points: 90 minutes, 2 hours 30 minutes, 4 hours, and 6 hours.
The secondary objective was to evaluate the safety and tolerability of a single dose of ASP8062 with or without alcohol. Secondary endpoints included the nature, frequency, and severity of adverse events (AEs), clinical laboratory tests (hematology, biochemistry, and urinalysis), vital signs (blood pressure and pulse), routine 12-lead electrocardiogram (ECG), Columbia-Suicide Severity Rating Scale (C-SSRS), and SpCh.
Exploratory objectives included evaluation of the general pharmacokinetic and pharmacodynamic parameters of ASP8062 and alcohol. Exploratory pharmacokinetic endpoints measured from ASP8062 plasma were time to peak plasma concentration (tmax), half-life in plasma (t>/2), apparent clearance (CL/F), and apparent volume of distribution during terminal phase after oral administration (Vz/F); tmax was the exploratory endpoint measured from alcohol plasma. Additional exploratory safety and tolerability endpoints were assessed by the Bond- Lader Visual Analogue Scales (VAS), Addiction Research Center Inventory Scale 49-item short form (ARCI-49), alcohol urge questionnaire (AUQ), drug effects questionnaire (DEQ-5), and a daytime somnolence scale.
Statistical analysis
A total of 20 subjects were enrolled to ensure that a minimum of 16 subjects completed the study. The pharmacokinetic analysis set (PKAS) was used for the analysis of all
pharmacokinetic data and consisted of all subjects who received at least one dose of study medication for which concentration data were available in order to facilitate derivation of at least one primary pharmacokinetic parameter of ASP8062. The pharmacodynamic analysis set (PDAS) was used for the analysis of all pharmacodynamic data and consisted of all subjects who received at least one dose of the test agents (alcohol and ASP8062) for which sufficient pharmacodynamic measurements were collected. The safety analysis set (SAF) was used for all summaries and analyses of the safety data and consisted of all subjects who received at least one dose of alcohol or ASP8062.
The pre- and postdose plasma concentration values of ASP8062 for one of the subjects during ASP8062 alone treatment was below the lower limit of quantification (LLOQ; 0.5 ng/mL) and thus were excluded from summary statistics. Additionally, following administration of ASP8062 alone, one subject had approximately 10-fold lower plasma concentrations of ASP8062 compared with other subjects and when compared with the subject's own concentrations during combination treatment; reasons for this low concentration of ASP8062 could not be determined. Therefore, an additional sensitivity analysis was conducted to reassess the PKAS by excluding this particular subject from the statistical assessments. The PKAS, excluding the subject who showed substantially lower plasma concentrations of ASP8062 following administration of ASP8062 alone (but showed similar ASP8062 exposure compared with other subjects following administration of ASP8062 in combination with alcohol), is presented in the main figures and tables; complete analyses including the potential outlier subject are provided in the supplemental figures and tables (Figures 15-17, Example 3 Table SI).
Descriptive statistics were used to summarize plasma pharmacokinetic parameters. To assess the effect of alcohol on the pharmacokinetics of ASP8062 and the effect of ASP8062 on the pharmacokinetics of alcohol, plasma exposures were evaluated bidirectionally and an analysis of variance (ANOVA) model with treatment, period, and sequence as fixed effects and subject as a random effect was fitted on natural logarithm -transformed AUCinf and Cmax. To assess the potential pharmacodynamic effect of ASP8062, the potential pharmacodynamic effect of alcohol, and the potential pharmacodynamic interaction between ASP8062 and alcohol, a mixed effects analysis of covariance in change from baseline over time with period, sequence, treatment, and baseline by period as fixed effects, subject as a random effect, and baseline as a covariate was used. The treatment differences and corresponding 90% confidence intervals
(Cis) were estimated.
Adverse events were coded using MedDRA v22.0. The number and percentage of subjects with treatment-emergent AEs (TEAEs, defined as an AE with onset at any time from first dosing until the last scheduled procedure), investigational product-related TEAEs, TEAEs leading to withdrawal of treatment, investigational product-related TEAEs leading to withdrawal of treatment, serious TEAEs, and investigational product-related serious TEAEs were summarized by system organ class (SOC), preferred term, and treatment condition.
RESULTS
Demographics and baseline characteristics
A total of 20 (100%) subjects (five subjects in each sequence) were randomized. All 20 subjects completed the study and were included in the PKAS, PDAS, and SAF. The demographic and baseline characteristics across treatment sequences (1-4) are summarized in Example 3 Table 1. The age of randomized subjects included in the study ranged from 25 to 55 years, with a median of 40.5 years across all sequences. The population consisted mainly of male subjects (70%) and was primarily Black or African American (65%).
Pharmacokinetic profile of ASP8062
Mean plasma concentration-time profiles of ASP8062 after administration alone and in the presence of ethanol are presented in Figure 15. Of the subjects administered ASP8062 alone before ASP8062 in combination with alcohol, five subjects had quantifiable predose samples of ASP8062 during the combination treatment ranging from 0.577 to 2.05 ng/mL, which contributed less than 1% of Cmax. Similarly, for the subjects administered ASP8062 in combination with alcohol before ASP8062 alone, four subjects had quantifiable predose samples of ASP8062 during treatment with ASP8062 alone ranging from 0.775 to 1.41 ng/mL.
When excluding the potential outlier subject who showed substantially lower plasma exposure of ASP8062 when treated with ASP8062 alone, but showed similar plasma exposure to other subjects when administered ASP8062 with alcohol, observed median tmax for ASP8062 remained unchanged after administration of alcohol (median tmax was 1.75 versus 1.52 hours) (Example 3 Table 2). Observed mean t>/2 for ASP8062 remained unchanged after administration of alcohol (mean t>/2 was 65.3 versus 68.0 hours). Mean values of apparent clearance (CL/F) appeared to be skewed when excluding the potential outlier subject; however,
this was not apparent with regard to AUC.
After administration of alcohol, a minimal increase in total exposure of ASP8062 was observed, with an AUCinf geometric least squares (LS) mean ratio (90% CI) of 105.22% (96.00, 115.34). In addition, a mild increase in peak plasma concentrations of ASP8062 was also observed with a Cmax geometric LS mean ratio (90% CI) of 124.91% (107.48, 145.17).
Pharmacokinetic profile of ethanol in combination with ASP8062
The plasma concentration of ethanol increased rapidly, based on visual inspection (Figure 15B) The observed median tmax for ethanol remained unchanged after administration of ASP8062 (median tmax 0.767 versus 0.634 hours) (Example 3 Table S2). The effect of ASP8062 on the AUCiast and Cmax of alcohol remained unchanged, with an AUCiast geometric LS mean ratio (90% CI) of 96.03% (86.42, 106.72) and Cmax geometric LS mean ratio (90% CI) of 95.50% (87.24, 104.56). The geometric intrasubject coefficient-of-variation (CV) for the AUCiast and Cmax of ASP8062 was 19.3% and 16.5%, respectively.
Pharmacodynamic parameters
Performance data from four assessments of the Cogstate battery were selected for evaluation of the cognitive pharmacodynamic profile of ASP8062 and alcohol. Mean Cogstate battery test results and changes from baseline are presented in Figure 16. Subjects who received ASP8062 alone showed numerically worse scores on the Identification, One-back, and GMLT tests compared with placebo up to 4 hours postdose (Example 3 Table S3), but did not show consistent or robust changes in performance on these tests when compared with placebo. Subjects who received alcohol alone showed worse performance on the Detection and GMLT tests compared with placebo up to 4 hours postdose and on the One-back test at 2.5 hours postdose (Example 3 Table S4). Subjects who received ASP8062 in combination with alcohol showed worse performance on the Identification and One-back tests compared with those who received alcohol alone up to 2.5 hours postdose (Example 3 Table 3). However, the maximum LS mean changes observed with the combination of ASP8062 and alcohol in the Detection test, Identification test, and GMLT tests were no more than 2-fold greater than the LS mean change with alcohol alone (Example 3 Table 3). A single ASP8062 dose in combination with alcohol resulted in numerically worse scores in the GMLT at 1.5 hours postdose and the One-Back test at 6 hours postdose compared with alcohol alone (Example 3 Table 4), but this apparent potentiation effect was not consistent.
In the postural stability tests, change from baseline data showed that subjects who received alcohol alone and ASP8062 in combination with alcohol tended to perform worse than subjects who received ASP8062 alone or placebo (Figure 17). However, subjects who received alcohol alone performed numerically worse at baseline than subjects who received the other treatment conditions. Subjects who received ASP8062 alone performed numerically worse than those who received placebo up to 4 hours postdose (Example 3 Table S5), while subjects who received alcohol alone performed numerically worse than placebo at 2.5 hours postdose (Example 3 Table S5). Subjects who received ASP8062 in combination with alcohol did numerically worse than those who received alcohol alone up to 4 hours postdose (Example 3 Table 5). No potentiation effect with the combination of ASP8062 and alcohol was observed at any time point (Example 3 Table 6). Furthermore, subjects administered alcohol alone and ASP8062 in combination with alcohol tended to perform worse than subjects administered ASP8062 alone or placebo.
Safety
A total of 22 TEAEs were reported for 10 (50.0%) subjects during the course of this study and the incidence of TEAEs was similar between treatment conditions. Of these, 16 TEAEs reported for six (30%) subjects were considered by the investigator to be related to ASP8062 or alcohol, and were mild in severity, except for three TEAEs of headache (reported for two subjects), which were considered to be moderate in severity. No deaths, serious AEs, or AEs that led to the withdrawal of treatment were reported throughout the study. The most commonly reported TEAEs were headache (n=4 subjects, 20%) and vomiting (n=3 subjects, 15%) (Example 3 Table 7). The most commonly reported potential abuse-related AE following administration of ASP8062 in combination with alcohol in any treatment condition was dizziness (n=2 subjects, 10%) within the SOC nervous system disorders. One subject administered alcohol alone reported dizziness and none of the subjects administered ASP8062 alone reported dizziness. All TEAEs associated with ASP8062, with the exception of hordeolum, recovered or resolved within 24 hours. The TEAEs reported for subjects administered ASP8062 in combination with alcohol occurred after administration of alcohol.
There were no clinically relevant changes in laboratory analyses, liver function tests, vital signs, or ECG measurements. No single event of suicidal ideation or suicidal behavior was reported (Example 3 Table S6). No clinically meaningful reduction in SpCh occurred during this study. None of the subjects had SpCh levels below 92% at any postbaseline time point (Example 3
Table S7)
When subjects were administered ASP8062 alone, there were no differences in feelings of alertness, calmness, or contentment based on the Bond-Lader Visual Analogue Scales (Example 3 Table S8); no subjective effects of psychoactive drugs based on ARCI-49 (Example 3 Table S9); no alcohol craving based on an AUQ (Example 3 Table S10); no increase in strength and desirability of substance drug effects (Example 3 Table Sil); and no mean changes in daytime somnolence from baseline (Example 3 Table S12) compared with subjects administered placebo. Generally, observed numerical mean changes from baseline for these safety-related assessments were greater in subjects administered both ASP8062 in combination with alcohol and alcohol alone compared with ASP8062 alone or the placebo/placebo condition.
DISCUSSION
GAB AB receptor PAMs represent a potential therapeutic alternative to conventional GAB AB receptor orthosteric agonists for treatment of substance abuse disorders because the PAMs enhance GAB AB receptor signaling by endogenous neurotransmitters without constitutive receptor stimulation. The resulting specific enhancement of GAB AB receptor activity may be associated with reduced side effects and mitigation of tolerance upon repeated administration. GAB AB receptors play a major role in various CNS functions; therefore, modulation of GABA transmission can have significant effects. However, the development of agonists targeting this receptor subtype has not translated into the degree of clinical success or regulatory approval that was anticipated due to neurologic complications, potential for abuse, and pharmacokinetic limitations. Development of GAB AB receptor PAMs with reduced potential for abuse and tolerance could address this unmet need. Accordingly, the primary objective of this study was to assess the potential for pharmacokinetic and pharmacodynamic interaction between ASP8062 and alcohol under single-dose conditions.
Current pharmacokinetic data suggest that alcohol minimally increases ASP8062 plasma concentrations, while alcohol plasma concentrations appear unaffected by ASP8062. The carryover effect was minimal for ASP8062 and alcohol. Median tmax and mean t/2 for ASP8062 remained unchanged after administration of alcohol, which suggests that the apparent increase in ASP8062 exposures (Cmax and AUCinf) may be due to an increase in the plasma concentration of ASP8062, rather than a decrease in the elimination of ASP8062. However, these conclusions
need to be viewed with caution due to the rapid elimination of ethanol relative to that of ASP8062. The absence of any pharmacokinetic effect of ethanol on ASP8062 is in agreement with reports for the pharmacokinetic interaction of alcohol on a K-opioid receptor antagonist (LY2456302) and a p-opioid receptor antagonist (GSK1521498) (Lowe et al., 2014). In contrast, ethanol coadministration with y-hydroxybutyrate (GHB), the precursor of GABA, resulted in higher GHB plasma concentration and longer elimination half-life, indicating possible enhanced bioavailability or reduced GHB clearance by ethanol (Thai et al., 2006). This effect of alcohol on the pharmacokinetic profile of GHB is unlikely to be of clinical significance and further supports the lack of pharmacokinetic effect of alcohol on GAB AB receptor modulators, including ASP8062.
Several studies have investigated the coadministration of baclofen with alcohol (Evans and Bisaga, 2009; Farokhnia et al., 2021; Farokhnia et al., 2017; Leggio et al., 2013). In the phase 1 study by Evans and Bisaga (2009), baclofen alone had minimal abuse liability in nontreatmentseeking heavy social drinkers and was relatively well tolerated and safe when given in combination with intoxicating doses of alcohol. Subsequent studies in nontreatment-seeking alcohol-dependent individuals by Leggio and colleagues demonstrated that while baclofen may have reduced alcohol consumption in certain subjects, the results suggested that it may serve as a substitute medication for AUD given it neither had an anticraving or antireinforcing effect on alcohol self-admini strati on (Farokhnia et al., 2017; Leggio et al., 2013). The overall results from the current ASP8062 study are in line with these studies, and, more importantly, further augment the safety profile of ASP8062, providing further justification to proceed to the next development phase in AUD patients. However, caution should be used in comparing these trials, as the current study was conducted in healthy individuals without significant alcohol- related problems.
In this study, one subject was considered a potential outlier due to substantially lower plasma exposure of ASP8062 when treated with ASP8062 alone. Although the total exposure of ASP8062 and peak plasma concentrations of ASP8062 were reduced when excluding the outlier, the difference in the geometric LS mean ratios was similar between the complete case set and the sensitivity analysis for the PKAS excluding the outlier. In addition to being an outlier when comparing the subject’s pharmacokinetics after administration of ASP8062 alone versus ASP8062 in combination with alcohol, this subject also appeared to be an outlier in the overall subject population of this study and across the entirety of the ASP8062 phase 1 clinical
experience.
Subjects who received ASP8062 alone did not experience any consistent or robust changes in cognition measurements when compared with those who received placebo. As expected, administration of alcohol alone led to impairment in psychomotor function and executive function assessments. Furthermore, administration of ASP8062 in combination with alcohol worsened performance on the cognitive test when compared with subjects who received alcohol alone. This suggests that there may be a numerically additive interaction between ASP8062 and alcohol. However, ASP8062 alone did not show any consistent or robust negative cognitive effects. Likewise, a consistent potentiation of the effect was not observed. The cognitive effects observed with ASP8062 alone and ASP8062 administered in combination with alcohol are consistent with the profile of CNS-penetrating medications (Chen et al., 2015; Evans and Bisaga, 2009; Morrison et al., 2018). The relatively mild impact on the tested pharmacodynamic assessments is in line with separate preliminary reports that a > -opioid receptor antagonist (LY2456302) and arginine vasopressin type IB receptor antagonist (ABT- 436) did not exacerbate cognitive impairment when administered with alcohol (Katz et al., 2016; Lowe et al., 2014). The effect of alcohol on cognitive measures is known to occur via a complex interplay between excitatory and inhibitory neurotransmitters, including dopamine, noradrenaline, endogenous opioids, GABA, glutamate, and serotonin (McIntosh and Chick, 2004). The promiscuous pharmacological effects of alcohol provide caution in extrapolating from acute drug-alcohol interactions to chronic drug-alcohol interactions.
Importantly, ASP8062 did not potentiate the effects of its combined administration with alcohol to the point of ataxia, which is observed with higher blood alcohol exposures. This is possibly due to lower baseline values in treatment with ASP8062 in combination with alcohol and placebo compared with ASP8062 alone and alcohol alone. When numerically greater impairment was observed for these tests, the effect in subjects administered ASP8062 in combination with alcohol was generally no more than two-fold greater than that observed in subjects administered alcohol alone. The numerically greater impairment in cognition observed with single doses of ASP8062 combined with alcohol compared with alcohol alone may not be observed with daily administration of ASP8062 and remains to be tested. As only a single 60- mg dose of ASP8062 was tested in this study, the pharmacodynamic effects may differ from single to multiple dose administration.
ASP8062 was safe and well -tolerated in this study. The safety findings observed in subjects administered alcohol alone were not augmented when ASP8062 was administered in combination with alcohol. Absence of AEs related to drug abuse potential (eg, somnolence, strength, and desirability of drug effects) from the combination of ASP8062 and alcohol were not observed, suggesting minimal concern for abuse potential with the combination. In contrast, GABA agonists often demonstrate treatment efficacy but have limited clinical application due to significant abuse potential or other safety issues. Importantly, ASP8062 did not affect blood oxygen saturation, including when combined with alcohol. This is a critical feature of ASP8062 as direct receptor agonism by GHB treatment alone decreased oxygen saturation levels and was further decreased when coadministered with ethanol (Thai et al., 2006).
The primary limitation of this study is the small sample size comprising healthy adults. Also, only one single oral dose of ASP8062 was administered. This study only aimed to assess any interaction between ASP8062 and alcohol under a single-dose setting in healthy adults. Therefore, no definitive conclusion about the pharmacokinetics, pharmacodynamics, and safety under a multiple-dose setting in patients with substance use disorder can be made based on the current data. Subjects who received alcohol alone performed numerically worse at baseline than subjects who received the other treatment conditions, which may have biased the change from baseline results. Also, subjects received ASP8062 and alcohol in the morning; therefore, we do not have information regarding the potential interaction between ASP8062 and alcohol if alcohol is administered after a single bedtime dose of ASP8062.
In summary, the current phase 1 study does not suggest risks of a potential interaction between ASP8062 and alcohol precluding future clinical studies in patients with AUD. Alcohol had a mild effect on increasing ASP8062 plasma concentration (Cmax but not AUC) and slight impairment on cognitive measurements, but these pharmacodynamic alterations were not observed with ASP8062 treatment alone. Importantly, a robust and consistent potentiation of cognitive impairment was not observed with the combination of ASP8062 and alcohol. The data from this study provides relevant pharmacokinetic, pharmacodynamic, and safety data to assess the potential risk of coadministration of ASP8062 and alcohol for future studies.
EXAMPLE 3 TABLES
Example 3 Table 2. Plasma Pharmacokinetic Parameters of ASP8062 After Administration Alone and in the Presence of Alcohol (Pharmacokinetic Analysis Set, Excluding 1 Outlier)
All subjects who received at least one dose of investigational product for which concentration data were available to facilitate derivation of at least one primary pharmacokinetic parameter of ASP8062.
*One subject had substantially low plasma concentrations of ASP8062 and one subject had plasma concentrations of ASP8062 below the LLOQ (0.5 ng/mL). One subject did not meet the number of halflives needed for the Lambda-z range to be acceptable; therefore, Lambda-z dependent parameters were excluded, and one subject did not show any quantifiable sample at all time points in the ASP8062 treatment group.
Abbreviations: %CV coefficient-of-variation percent; AUC24 area under the concentration-time curve from the time of dosing to 24 hours postdose; AUC’mr. area under the concentration-time curve from the
time of dosing extrapolated to time infinity; AUCiast, area under the concentration-time curve from the time of dosing to the last measurable concentration; CL/F apparent clearance; CmaX, maximum concentration; SD, standard deviation; ti/2, half-life; tmax, time to peak plasma concentration; VzF apparent volume of distribution during terminal phase after oral administration.
Example 3 Table 3. Cogstate Battery Statistical Assessment of Potential Pharmacodynamic Interaction Between ASP8062 and Alcohol
One subject was unable to complete the Cogstate tests for the 1.5-hour time point due to adverse events following administration of placebo ASP8062 in combination with alcohol.
Abbreviations: CI, confidence interval; LS, least squares.
Example 3 Table 4. Cogstate Battery Statistical Assessment of Potentiation Effect of ASP8062 in Combination with Alcohol
Abbreviations: CI, confidence interval; LS, least squares.
Example 3 Table 5. Postural Stability Statistical Assessment of Pharmacodynamic Interaction Between ASP8062 and Alcohol
Abbreviations: CI, confidence interval; LS, least squares.
Example 3 Table 6. Postural Stability Statistical Assessment of Potentiation Effect of ASP8062 in Combination with Alcohol
Abbreviations: CI, confidence interval; LS, least squares.
Example 3 Table 7. Incidence of Treatment-Related Adverse Events
Example 3 Table SI. Plasma Pharmacokinetic Profile of ASP8062 Alone or in Combination with Alcohol for Complete Subject Data Set
All subjects who received at least one dose of investigational product for which concentration data were available to facilitate derivation of at least one primary pharmacokinetic parameter of ASP8062.
*One subject had substantially low plasma concentrations of ASP8062 and one subject had plasma concentrations of ASP8062 below the LLOQ (0.5 ng/mL).
"Five subjects had quantifiable predose samples of ASP8062 during the combination treatment ranging from 0.577-2.05 ng/mL, which contributed less than 1% of Cmax.
Abbreviations: %CV, coefficient-of-variation percent; AUCinf, area under the concentration-time curve from the time of dosing extrapolated to time infinity; AUCiast, area under the concentration-time curve from the time of dosing to the last measurable concentration; CL/F, apparent clearance; Cmax, maximum concentration; LLOQ, lower limit of quantification; SD, standard deviation; ti/2, half-life; tmax, time to peak plasma concentration; VzF, apparent volume of distribution during terminal phase after oral administration.
Example 3 Table S2. Plasma Pharmacokinetic Parameters of Ethanol After Administration of Alcohol Alone and in the Presence of ASP8062
Abbreviations: AUCiast, area under the concentration-time curve from the time of dosing to the last measurable concentration; Cmax, maximum concentration; tmax, time to peak plasma concentration.
Example 3 Table S3. Cogstate Battery Statistical Assessment of Potential Pharmacodynamic Effect of
ASP8062
Abbreviations: CI, confidence interval; LS, least squares. Example 3 Table S4. Cogstate Battery Statistical Assessment of Potential Pharmacodynamic Effect of Alcohol
Abbreviations: CI, confidence interval; LS, least squares.
Example 3 Table S5. Postural Stability Statistical Assessment of Potential Pharmacodynamic Effect of ASP8062 and Alcohol
Abbreviations: CI, confidence interval; LS, least squares.
Example 3 Table S6. C-SSRS Categorized Results of ASP8062 and Alcohol (Safety Analysis Set)
Abbreviation: C-SSRS, Columbia-Suicide Severity Rating Scale.
Example 3 Table S7. Percent Blood Oxygen Saturation by Treatment Condition
Abbreviation: SD, standard deviation.
Abbreviations: SD, standard deviation; VAS, Visual Analogue Scale.
Example 3 Table S9. ARCI-49 Questionnaire Subscale Scores for ASP8062 and Alcohol (Safety Analysis Set)
Abbreviations: ARCI-49, Addiction Research Center Inventory 49-item questionnaire; SD, standard deviation.
Example 3 Table S10. Alcohol Urge Questionnaire Total Scores of ASP8062 and Alcohol (Safety Analysis Set)
*n=19.
Abbreviation: SD, standard deviation.
Example 3 Table Sil. Drug Effects Questionnaire Scores for ASP8062 and Alcohol (Safety Analysis Set)
Example 3 Table S12. Daytime Somnolence Scale Ratings Results for ASP8062 and Alcohol (Safety Analysis Set)
The data in the three tables below shows blood oxygen saturation mean values and change from baseline, as well as the minimum values and maximum values. No subjects were observed with SpO2 levels less than 90% at any post-baseline time point. Thus, no individual subjects showed a serious decrease in blood oxygen saturation at any time point.
The entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes.
EQUIVALENTS
The disclosure can be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting on the disclosure described herein. Scope of the disclosure is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.
References
Addolorato, G., Leggio, L., Ferrulli, A., Cardone, S., Vonghia, L., Mirijello, A., 2009.
Effectiveness and safety of baclofen for maintenance of alcohol abstinence in alcoholdependent patients with liver cirrhosis: randomised, double-blind controlled study. Lancet 370, 1915-1922.
Algera, M.H., Kamp, J., Schrier, R.V.D., Velzen, M.V., Niesters, M., Aarts, L., Dahan, A., Olofsen, E., 2019. Opioid-induced respiratory depression in humans: a review of pharmacokinetic-pharmacodynamic modelling of reversal. Brit. J. Anesthesia 122, el68- el78.
Akhondzadeh, S., Ahmadi-Abhari, S.A., Assadi, S.M., Shabestari, O.L., Kashani, A.R., Farzanehgan, Z.M., 2000. Double-blind randomized controlled trial of baclofen vs. clonidine in the treatment of opiates withdrawal. J. Clin. Pharm. Ther. 25, 347-353.
Assadi, S.M., Radgoodarzi, and Ahmadi-Abhari, S.A., 2003. Baclofen for maintenance treatment of opioid dependence: A randomized double-blind placebo-controlled clinical trial. BMC Psychiatry 3, 16, 1-10.
Bexis, S., Ong, J., White. J., 2003. Attenuation of morphine withdrawal signs by the GAGAB receptor agonist baclofen. Life Sci. 70, 395-401.
Blanco, C., Volkow, N.D., 2019. Management of opioid use disorder in the USA: present status
and future directions. Lancet 393, 1760-1772.
Bowery, N.G., Bettier, B., Froestl, W., Gallagher, J.P., Marshall, F., Raiteri, M., Raiteri, M., Bonner, T.I., Enna, J., 2002. International Union of Pharmacology. XXXIII. Mammalian y-aminobutyric acids receptors: structure and function. Pharmacol. Rev. 54, 247-264.
Compton, W.M., Jones, C.M., 2019. Epidemiology of the U.S. opioid crisis: the importance of the vector. Ann. N. Y. Acad. Sci. 1451, 1, 130-143.
Dario, A., Tomei, G., 2019. A benefit-risk assessment of baclofen in severe spinal spasticity. Drug Safety 27, 799-818.
Deneau G, Yanagita T, Seevers MH. Self-administration of psychoactive substances by the monkey. Psychopharmacologia 1969;16:30-48.
Fadda, P., Scerma, M., Fresu, A., Collu, M., Fratta, W., 2003. Baclofen antagonizes nicotine-, ***e-, and morphine-induced dopamine release in the nucleus accumbens of rat. Synapse 50, 1-6.
Filip, M., Frankowska, M., Przegalinski, E., 2007. Effects of GAB AB receptor antagonist, agonists and allosteric positive modulator on the ***e-induced self-administration and drug discrimination. Eur. J. Pharmacol. 574, 148-157.
Filip, M., Frankowska, M., Sadakierska-Chudy, A., Suder, A., Szumiec, L., Mierzejewski, P., Bienkowski, P., Przegalinski, E., Cryan, J.F., 2015. GAB AB receptors as a therapeutic strategy in substance use disorders: Focus on positive allosteric modulators. Neuropharmacology 88, 36-47.
Fujiwara, A., lino, M., Sasaki, M., 2016. Relationship between the dose to produce reinforcing effect and that of gross behavioral effects in rhesus monkeys. J. Drug Abuse 2, 2, 1-9. lizuka, H., Sasaki, K., Odagiri, N., Obo, M., Imaizumi, M., Atai, H., 2010. Measurement of respiratory function using whole-body plethysmography in unanesthetized and unrestrained nonhuman primates. J. Toxicol. Sci. 35, 863-870.
Liang, J.H., Chen, F., Krstew, E., Cowen, M.S., Carroll, F.Y., Crawford, D., Beart, P.M., Lawrence, A. J. 2006. The GAB AB receptor allosteric modulator CGP7930, like baclofen,
reduces operant self-administration of ethanol in alcohol-preferring rats.
Neuropharmacology 50, 632-639.
Lobina, C., Maccioni, P., Lorrai, I., Zaru, A., Collu, M., Carai, M.A.M., Brizzi, A., Mugnaini, C., Gessa, G.L., Corelli, F., Colombo, G., 2021. Suppressing effect of the novel positive allosteric modulator of the GAB AB receptor, COR659, on locomotor hyperactivity induced by different drugs of abuse. Behav. Brain Research 400, 113045.
Mattick, R.P., Breen, C., Kimber, J., Davoli, M., 2009. Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence. Cochrane Database Sy st. Rev. 3, CD002209.
Mattick, R.P., Breen, C., Kimber, J., Davoli, M., 2014. Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. Cochrane Database Syst. Rev. 2, CD002207.
Mototsugu Ito, Anna Spence, Mary Beth Blauwet, Nakyo Heo, Ronald Goldwater, Paul Maruff, Gerard J Marek, A phase 1 study to assess potential interaction between ASP8062 and alcohol in healthy adult subjects, J Psychopharmacol 2022 Jun;36(6):756-767. doi: 10.1177/02698811211058967. Epub 2022 Jan 7.
Murai, N., Kondo, Y., Akuzawa, S., Mihara, T., Shiraishi, N., Kakimoto, S., Matsumoto, M., 2019. A novel GAB AB receptor positive allosteric modulator, ASP8062, exerts analgesic effects in a rat model of fibromyalgia. Eur. J. Pharmacol. 865, 172750.
Rasmussen, K., White, D.A., Acri, J.B., 2019. NIDA’s medication development priorities in response to the opioid crisis: ten most wanted. Neuropsychopharmacology 44, 657-659.
Saharei, H., Etemadi, L., Rostami, P., Pourmotabbed, A., Zarrindast, M.R., Shams, J., Ghoshooni, H., Noroozzadeh, A., Esfandiari, B., Salimi, S.H., 2009. GAB AB receptors within the ventral tegmental area are involved in the expression and acquisition of morphine-induced place preference in morphine-sensitized rats. Pharmacol. Biochem. Behav. 91, 409-416.
Schwartz, R.P., Gryczynski, J., O'Grady, K.E., Sharfstein, J.M., Warren, G., Olsen, Y., et al. 2013 Opioid agonist treatments and heroin overdose deaths in Baltimore, Maryland, 1995-2009. Am. J. Public Health 10, 917-922.
Shoptaw, S., Yang, X., Rotheram-Fuller, E.J., Hsieh, Y.C.M., Kintaudi, P.C., Charuvastra, V.C. and Ling W., 2003. Randomized placebo-controlled trial of baclofen for ***e dependence: preliminary effects for individuals with chronic patterns of ***e use. J. Clin. Psychiatry 64, 1440-1448.
Smith, M.A., 2020. Nonhuman animal models of substance use disorders: translational value and utility to basic science. Drug Alcohol Depend. 206, 1-13.
Spangel, R., Weiss, F., 1999. The dopamine hypothesis of reward: past and current status. Trends Neursci. 22, 521-527.
Strang, J., Volkow, N.D., Degenhardt, L., Hickman, M., Johnson, K., Koob, G.F., Marshall, B.D.L., Tyndall, M., Walsh, S.L., 2020. Opioid use disorder. Nat. Rev. Disease Primers 6, 3.
Tsuji, M., Nakagawa, Y., Ishibashi, Y., Yoshii, T., Takashima, T., Shimada, M., Suzuki, T., 1996. Activation of ventral tegmental GAB AB receptors inhibits morphine-induced place preference in rats. Eur. J. Pharmacol. 313, 169-173.
Walzer, M., Marek, G.J., Wu, R.S., Nagata, M., Han, D., 2020. Single- and multiple-dose safety, tolerability, and pharmacokinetic profiles of ASP8062: results from 2 phase 1 studies. Clin. Pharmacol. Drug Development 9, 297-306.
Walzer, M., Wu, R., Ahmad, M., Freeman, J., Zammit, G., Marek, G.J., 2021. A randomized phase 1 single-dose polysomnography study of ASP8062, a GAB AB receptor positive allosteric modulator. Psychopharmacology s00213-020-05738-y
Xi, Z.X., Stein, EA., 1999. Baclofen inhibits heroin self-administration behavior and mesolimbic dopamine release. J. Pharmacol. Exp. Ther. 290, 1369-1374.
Yoon, S.S., Lee, B.H., Kim, H.S., Choi, K.H., Yun, J., Jang, E.Y., Shim, I., Kim, J. A., Kim, M.R., Yang, C.H., 2007. Potential roles of GABA receptors in morphine selfadministration in rats. Neurosci. Lett. 428, 33-37.
Zarrindast, M.R., Mosa- Ahmadi, E., 1999. Effects of GABAergic system on naloxone-induced jumping in morphine-dependent mice. Eur. J. Pharmacol. 381, 129-133.
Zoorob, R., Alicia, K., Grubb, A., Mejia, M., 2018. Buprenorphine therapy for opioid use
disorder. Am. Fam. Physician 97, 313-320.
Addolorato G. et al., Curr Pharm Des 16(10): 2113-2117 (2010).
Agabio et al., Recent Pat CNS Drug Discov 7(2): 113-128 (2012).
Agabio et al., Lancet Psychiatry 5(12): 957-960 (2018).
Augier E. et al., Alcohol Alcohol 56(2): 139-148 (2021).
Augier E. et al., Neuropsychopharmacology 42(9): 1789-1799 (2017).
Chen X, Jacobs G, de Kam ML, et al. (2015) AZD6280, a novel partial gamma-aminobutyric acid A receptor modulator, demonstrates a pharmacodynamically selective effect profile in healthy male volunteers. J Clin Psychopharmacol 35(1): 22-33.
Evans SM and Bisaga A (2009) Acute interaction of baclofen in combination with alcohol in heavy social drinkers. Alcohol Clin Exp Res 33(1): 19-30.
Evenseth LSM, Gabrielsen M and Sylte I (2020) The GABA(B) Receptor- Structure, Ligand Binding and Drug Development. Molecules 25(13).
Farokhnia M, Deschaine SL, Sadighi A, et al. (2021) A deeper insight into how GABA-B receptor agonism via baclofen may affect alcohol seeking and consumption: lessons learned from a human laboratory investigation. Mol Psychiatry 26(2): 545-555.
Farokhnia M, Schwandt ML, Lee MR, et al. (2017) Biobehavioral effects of baclofen in anxious alcohol-dependent individuals: a randomized, double-blind, placebo-controlled, laboratory study. Transl Psychiatry 7(4): el 108.
Foerster BR, Petrou M, Edden RA, et al. (2012) Reduced insular y-aminobutyric acid in fibromyalgia. Arthritis Rheum 64(2): 579-583.
Haile CN, Carper BA, Nolen TL, et al. (2021) The GAB AB receptor positive allosteric
modulator ASP8062 reduces operant alcohol self-administration in male and female Sprague Dawley rats. Psychopharmacology (Berl). Epub ahead of print 2021/07/07. DOI: 10.1007/s00213-021-05881-0.
Holajova M and Franek M (2018) Effect of short- and long-term administration of baclofen on spatial learning and memory in rats. Physiol Res 67(1): 133-141.
Katz DA, Locke C, Liu W, et al. (2016) Single-Dose Interaction Study of the Arginine Vasopressin Type IB Receptor Antagonist ABT-436 and Alcohol in Moderate Alcohol Drinkers. Alcohol Clin Exp Res 40(4): 838-845.
Leggio L, Zywiak WH, McGeary JE, et al. (2013) A human laboratory pilot study with baclofen in alcoholic individuals. Pharmacol Biochem Behav 103(4): 784-791.
Lowe SL, Wong CJ, Witcher J, et al. (2014) Safety, tolerability, and pharmacokinetic evaluation of single- and multiple-ascending doses of a novel kappa opioid receptor antagonist LY2456302 and drug interaction with ethanol in healthy subjects. J Clin Pharmacol 54(9): 968- 978.
Maccioni P and Colombo G (2019) Potential of GABA(B) Receptor Positive Allosteric Modulators in the Treatment of Alcohol Use Disorder. CNS Drugs 33(2): 107-123.
Maccioni P, Fara F, Lorrai I, et al. (2019) Suppressing effect of CMPPE, a new positive allosteric modulator of the GAB AB receptor, on alcohol self-administration and reinstatement of alcohol seeking in rats. Alcohol 75: 79-87.
May LT, Avlani VA, Sexton PM, et al. (2004) Allosteric modulation of G protein-coupled receptors. Curr Pharm Des 10(17): 2003-2013.
McIntosh C and Chick J (2004) Alcohol and the nervous system. J Neurol Neurosurg Psychiatry 75 Suppl 3(Suppl 3): iii 16-21.
Morrison RL, Fedgchin M, Singh J, et al. (2018) Effect of intranasal esketamine on cognitive functioning in healthy participants: a randomized, double-blind, placebo-controlled study.
Psychopharmacology (Berl) 235(4): 1107-1119.
Olsen R (2002) GABA. In: Kenneth L. Davis DC, Joseph T. Coyle, and Charles Nemeroff. (ed) Neuropsychopharmacology: The Fifth Generation of Progress. American College of Neuropsychopharmacology: Lippincott, Williams, & Wilkins, Philadelphia, Pennsylvania, 2002 pp.159-167.
Pierce M, Sutterland A, Beraha EM, et al. (2018) Efficacy, tolerability, and safety of low-dose and high-dose baclofen in the treatment of alcohol dependence: A systematic review and metaanalysis. Eur Neuropsychopharmacol 28(7): 795-806.
Pin JP and Prezeau L (2007) Allosteric modulators of GABA(B) receptors: mechanism of action and therapeutic perspective. Curr Neuropharmacol 5(3): 195-201.
Thai D, Dyer JE, Benowitz NL, et al. (2006) Gamma-hydroxybutyrate and ethanol effects and interactions in humans. J Clin Psychopharmacol 26(5): 524-529.
Varani AP, Aso E, Moutinho LM, et al. (2014) Attenuation by baclofen of nicotine rewarding properties and nicotine withdrawal manifestations. Psychopharmacology (Berl) 231(15): 3031- 3040.
Vengeliene V, Takahashi TT, Dravolina OA, et al. (2018) Efficacy and side effects of baclofen and the novel GABA(B) receptor positive allosteric modulator CMPPE in animal models for alcohol and ***e addiction. Psychopharmacology (Berl) 235(7): 1955-1965.
Claims
We claim:
1. A method of treating opioid use disorder in a patient in need thereof, the method comprising administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder and that does not cause respiratory depression in the patient.
2. A method according to claim 1, wherein respiratory depression is determined by measuring the difference, prior to and following administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof, in a parameter selected from end tidal CO2, blood oxygen saturation, or observed respiratory rate.
3. A method of treating opioid use disorder in a patient in need thereof, the method comprising: i. identifying and/or selecting a patient having opioid use disorder; and ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder and that does not cause respiratory depression in the patient.
4. A method of treating opioid use disorder in a patient in need thereof, the method comprising: i. determining a first respiratory status in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder; and iii. determining a second respiratory status in the patient; wherein the second respiratory status is not lower than the first respiratory status.
5. A method of treating opioid use disorder in a patient in need thereof, the method comprising: i. identifying and/or selecting a patient having opioid use disorder; ii. determining a first respiratory status in the patient; iii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder; and
iv. determining a second respiratory status in the patient; wherein the second respiratory status is not lower than the first respiratory status.
6. The method of claim 1 or 2, wherein the respiratory depression is determined by measuring blood oxygen saturation in the patient.
7. The method of claim 4 or 5, wherein the first respiratory status and the second respiratory status are determined by measuring blood oxygen saturation in the patient.
8. The method of claim 1, 2 or 3, wherein the respiratory status is determined by measuring end tidal CO2 in the patient.
9. The method of claim 4 or 5, wherein the first respiratory status and the second respiratory status are determined by measuring end tidal CO2 in the patient.
10. A method of treating opioid use disorder in a patient in need thereof, the method comprising administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder and that does not decrease blood oxygen saturation in the patient.
11. A method of treating opioid use disorder in a patient in need thereof, the method comprising: i. identifying and/or selecting a patient having opioid use disorder; and ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder and that does not decrease blood oxygen saturation in the patient.
12. A method of treating opioid use disorder in a patient in need thereof, the method comprising: i. determining a first blood oxygen saturation in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder; and
iii. determining a second blood oxygen saturation in the patient; wherein the second blood oxygen saturation is not lower than the first blood oxygen saturation.
13. A method of treating opioid use disorder in a patient in need thereof, the method comprising: i. identifying and/or selecting a patient having opioid use disorder; ii. determining a first blood oxygen saturation in the patient; iii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder; and iv. determining a second blood oxygen saturation in the patient; wherein the second blood oxygen saturation is not lower than the first blood oxygen saturation.
14. A method of treating opioid use disorder in a patient in need thereof, the method comprising administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder and that does not increase end tidal CO2 in the patient.
15. A method of treating opioid use disorder in a patient in need thereof, the method comprising: i. identifying and/or selecting a patient having opioid use disorder; and ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder and that does not increase end tidal CO2 in the patient.
16. A method of treating opioid use disorder in a patient in need thereof, the method comprising: i. determining a first end tidal CO2 in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder; and iii. determining a second end tidal CO2 in the patient; wherein the second end tidal CO2 is not higher than the first end tidal CO2.
17. A method of treating opioid use disorder in a patient in need thereof, the method comprising: i. identifying and/or selecting a patient having opioid use disorder; ii. determining a first end tidal CO2 in the patient; iii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder; and iv. determining a second end tidal CO2 in the patient; wherein the second end tidal CO2 is not higher than the first end tidal CO2.
18. The method of any one of the preceding claims, wherein the compound of Formula (I) or pharmaceutically acceptable salt thereof is administered in an amount equal to about 6.25 mg to about 50 mg per day.
19. The method of any one of the preceding claims, wherein the opioid addiction disorder is addiction to an opioid selected from diacetylmorphine (heroin), fentanyl, carfentanil, hydrocodone, hydromorphone, meperidine, methadone, morphine, a metabolite of morphine, oxycodone, oxymorphone, propoxyphene, and tramadol.
20. A method of treating opioid use disorder in a patient in need thereof, the method comprising administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder and that does not depress respiration in the patient beyond the level of respiratory depression observed with buprenorphine, naxolone, or a combination thereof.
21. A method of treating opioid use disorder in a patient in need thereof, wherein the patient is being treated with buprenorphine, naxolone, or a combination thereof, the method comprising administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the opioid use disorder and that does not decrease respiratory rate in the patient.
22. A method of treating opioid use disorder in a patient in need thereof, the method comprising: i. determining a first respiratory status in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a first amount that is effective in treating the opioid use disorder; iii. determining that a second respiratory status in the patient following administration is not lower than the first respiratory status; and iv. administering to the patient the compound in a second amount that is effective in treating the opioid use disorder; wherein the first amount and the second amount are the same or different.
23. A method of treating opioid use disorder in a patient in need thereof, the method comprising: i. determining a first respiratory status in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a first amount that is effective in treating the opioid use disorder; iii. determining that a second respiratory status in the patient following administration is lower than the first respiratory status; and iv. administering to the patient the compound in a second amount that is effective in treating the opioid use disorder; wherein the second amount is lower than the first amount.
24. A method of treating opioid use disorder in a patient in need thereof, the method comprising: i. determining a first respiratory status in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically
acceptable salt thereof, in a first amount that is effective in treating the opioid use disorder; iii. determining that a second respiratory status in the patient following administration is lower than the first respiratory status; and iv. discontinuing administration of the compound to the patient. The method of any one of the preceding claims, wherein the method reduces the severity of a symptom of the opioid use disorder. The method of any one of the preceding claims, wherein the method reduces the severity of a symptom of the opioid use disorder by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35% or at least 40% . The method of any one of the preceding claims, wherein the method determining the Cumulative Distribution Function (CDF) of the percentage of samples of urine of the patient that are negative for opioids. The method of claim 27, wherein the patient has at least 80% clean urines by frequency. The method of claim 27, wherein the patient has less than 20% of opioids in urine by frequency. A method of treating alcohol use disorder in a patient in need thereof, the method comprising administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder and that does not cause respiratory depression in the patient. A method of treating alcohol use disorder in a patient in need thereof, the method comprising: i. identifying and/or selecting a patient having alcohol use disorder; and ii. administering to the patient the compound of Formula (I), or a pharmaceutically
acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder and that does not cause respiratory depression in the patient.
32. A method of treating alcohol use disorder in a patient in need thereof, the method comprising: i. determining a first respiratory status in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder; and iii. determining a second respiratory status in the patient; wherein the second respiratory status is not lower than the first respiratory status.
33. A method of treating alcohol use disorder in a patient in need thereof, the method comprising: i. identifying and/or selecting a patient having alcohol use disorder; ii. determining a first respiratory status in the patient; iii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder; and iv. determining a second respiratory status in the patient; wherein the second respiratory status is not lower than the first respiratory status.
34. A method of treating alcohol use disorder in a patient in need thereof, the method comprising administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder and that does not decrease blood oxygen saturation in the patient.
35. A method of treating alcohol use disorder in a patient in need thereof, the method comprising: i. identifying and/or selecting a patient having alcohol use disorder; and ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder and that does not decrease blood oxygen saturation in the patient.
36. A method of treating alcohol use disorder in a patient in need thereof, the method comprising: i. determining a first respiratory status in the patient; ii. determining a first blood oxygen saturation in the patient;\ iii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder; and iv. determining a second blood oxygen saturation in the patient; wherein the second blood oxygen saturation is not lower than the first blood oxygen saturation.
37. A method of treating alcohol use disorder in a patient in need thereof, the method comprising: i. identifying and/or selecting a patient having alcohol use disorder; ii. determining a first blood oxygen saturation in the patient; iii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder; and iv. determining a second blood oxygen saturation in the patient; wherein the second blood oxygen saturation is not lower than the first blood oxygen saturation.
38. A method of treating alcohol use disorder in a patient in need thereof, the method comprising administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder and that does not increase end tidal CO2 in the patient.
39. A method of treating alcohol use disorder in a patient in need thereof, the method comprising: i. identifying and/or selecting a patient having alcohol use disorder; and ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder and that does not increase end tidal CO2 in the patient.
40. A method of treating alcohol use disorder in a patient in need thereof, the method comprising:
i. determining a first end tidal CO2 in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder; and iii. determining a second end tidal CO2 in the patient; wherein the second end tidal CO2 is not higher than the first end tidal CO2.
41. A method of treating alcohol use disorder in a patient in need thereof, the method comprising: i. identifying and/or selecting a patient having alcohol use disorder; ii. determining a first end tidal CO2 in the patient; iii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder; and iv. determining a second end tidal CO2 in the patient; wherein the second end tidal CO2 is not higher than the first end tidal CO2.
42. A method of treating alcohol use disorder in a patient in need thereof, the method comprising administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the alcohol use disorder and that does not depress respiration in the patient beyond the level of respiratory depression observed with buprenorphine, naxolone, or a combination thereof.
43. A method of treating alcohol use disorder in a patient in need thereof, the method comprising: i. determining a first respiratory status in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a first amount that is effective in treating the alcohol use disorder; iii. determining that a second respiratory status in the patient following administration is not lower than the first respiratory status; and iv. administering to the patient the compound in a second amount that is effective in treating the alcohol use disorder;
wherein the first amount and the second amount are the same or different.
44. A method of treating alcohol use disorder in a patient in need thereof, the method comprising: i. determining a first respiratory status in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a first amount that is effective in treating the alcohol use disorder; iii. determining that a second respiratory status in the patient following administration is lower than the first respiratory status; and iv. administering to the patient the compound in a second amount that is effective in treating the alcohol use disorder; wherein the second amount is lower than the first amount.
45. A method of treating alcohol use disorder in a patient in need thereof, the method comprising: i. determining a first respiratory status in the patient; ii. administering to the patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a first amount that is effective in treating the alcohol use disorder; iii. determining that a second respiratory status in the patient following administration is lower than the first respiratory status; and iv. discontinuing administration of the compound to the patient.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US202163237701P | 2021-08-27 | 2021-08-27 | |
US63/237,701 | 2021-08-27 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2023028519A2 true WO2023028519A2 (en) | 2023-03-02 |
WO2023028519A3 WO2023028519A3 (en) | 2023-04-20 |
Family
ID=83439181
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2022/075393 WO2023028519A2 (en) | 2021-08-27 | 2022-08-24 | Methods of treating substance use disorder |
Country Status (2)
Country | Link |
---|---|
TW (1) | TW202327616A (en) |
WO (1) | WO2023028519A2 (en) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9051339B2 (en) | 2013-10-17 | 2015-06-09 | Astellas Pharma Inc. | Sulfur-containing bicyclic compound |
-
2022
- 2022-08-24 WO PCT/US2022/075393 patent/WO2023028519A2/en unknown
- 2022-08-26 TW TW111132339A patent/TW202327616A/en unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9051339B2 (en) | 2013-10-17 | 2015-06-09 | Astellas Pharma Inc. | Sulfur-containing bicyclic compound |
Non-Patent Citations (61)
Title |
---|
ADDOLORATO G ET AL., CURR PHARM DES, vol. 16, no. 10, 2010, pages 2113 - 2117 |
ADDOLORATO, G., LEGGIO, L., FERRULLI, A., CARDONE, S., VONGHIA, L., MIRIJELLO, A.: "Effectiveness and safety of baclofen for maintenance of alcohol abstinence in alcohol-dependent patients with liver cirrhosis: randomised, double-blind controlled study", LANCET, vol. 370, 2009, pages 1915 - 1922, XP022379071, DOI: 10.1016/S0140-6736(07)61814-5 |
AGABIO ET AL., LANCET PSYCHIATRY, vol. 5, no. 12, 2018, pages 957 - 960 |
AGABIO ET AL., RECENT PAT CNS DRUG DISCOV, vol. 7, no. 2, 2012, pages 113 - 128 |
AKHONDZADEH, S., AHMADI-ABHARI, S.A., ASSADI, S.M., SHABESTARI, O.L., KASHANI, A.R FARZANEHGAN, Z.M.: "Double-blind randomized controlled trial of baclofen vs. clonidine in the treatment of opiates withdrawal", J. CLIN. PHARM. THER, vol. 25, 2000, pages 347 - 353 |
ALGERA, M.H., KAMP, J., SCHRIER, R.V.D., VELZEN, M.V., NIESTERS, M., AARTS, L., DAHAN, A.OLOFSEN, E: "Opioid-induced respiratory depression in humans: a review of pharmacokinetic-pharmacodynamic modelling of reversal", BRIT. J. ANESTHESIA, vol. 122, 2019, pages e168 - el78 |
ASSADI, S.M., RADGOODARZIAHMADI-ABHARI, S.A: "Baclofen for maintenance treatment of opioid dependence: A randomized double-blind placebo-controlled clinical trial", BMC PSYCHIATRY, vol. 3, no. 16, 2003, pages 1 - 10 |
AUGIER E. ET AL., ALCOHOL ALCOHOL, vol. 56, no. 2, 2021, pages 139 - 148 |
AUGIER E. ET AL., NEUROPSYCHOPHARMACOLOGY, vol. 42, no. 9, 2017, pages 1789 - 1799 |
BEXIS, S., ONG, J., WHITE. J.: "Attenuation of morphine withdrawal signs by the GAGAB receptor agonist baclofen.", LIFE SCI, vol. 70, 2003, pages 395 - 401 |
BLANCO, CVOLKOW, N.D: "Management of opioid use disorder in the USA: present status and future directions", LANCET, vol. 393, 2019, pages 1760 - 1772, XP085670443, DOI: 10.1016/S0140-6736(18)33078-2 |
BOWERY, N.G., BETTLER, B., FROESTL, W., GALLAGHER, J.P., MARSHALL, F., RAITERI, M., RAITERI, M BONNER, T.I., ENNA, J: "International Union of Pharmacology. XXXIII. Mammalian y-aminobutyric acid receptors: structure and function", PHARMACOL. REV, vol. 54, 2002, pages 247 - 264, XP002289606, DOI: 10.1124/pr.54.2.247 |
CHEN XJACOBS GKAM ML ET AL.: "AZD6280, a novel partial gamma-aminobutyric acid A receptor modulator, demonstrates a pharmacodynamically selective effect profile in healthy male volunteers", J CLIN PSYCHOPHARMACOL, vol. 35, no. 1, 2015, pages 22 - 33 |
COMPTON, W.M., JONES, C.M: "Epidemiology of the U.S. opioid crisis: the importance of the vector", ANN. N. Y. ACAD. SCI, vol. 1451, no. 1, 2019, pages 130 - 143, XP071410689, DOI: 10.1111/nyas.14209 |
DARIO, A., TOMEI, G: "A benefit-risk assessment of baclofen in severe spinal spasticity.", DRUG SAFETY, vol. 27, 2019, pages 799 - 818 |
DENEAU G, YANAGITA T, SEEVERS MH.: "Self-administration of psychoactive substances by the monkey", PSYCHOPHARMACOLOGIA, vol. 16, 1969, pages 30 - 48 |
EVANS SMBISAGA A: "Acute interaction of baclofen in combination with alcohol in heavy social drinkers", ALCOHOL CLIN EXP RES, vol. 33, no. 1, 2009, pages 19 - 30, XP071476410, DOI: 10.1111/j.1530-0277.2008.00805.x |
EVENSETH LSMGABRIELSEN MSYLTE I: "The GABA(B) Receptor-Structure, Ligand Binding and Drug Development", MOLECULES, vol. 25, no. 13, 2020 |
FADDA, P., SCERMA, M., FRESU, A., COLLU, M., FRATTA, W: " Baclofen antagonizes nicotine-***e-, and morphine-induced dopamine release in the nucleus accumbens of rat.", SYNAPSE, vol. 50, 2003, pages 1 - 6 |
FAROKHNIA MDESCHAINE SLSADIGHI A ET AL.: "A deeper insight into how GABA-B receptor agonism via baclofen may affect alcohol seeking and consumption: lessons learned from a human laboratory investigation", MOL PSYCHIATRY, vol. 26, no. 2, 2021, pages 545 - 555, XP037354845, DOI: 10.1038/s41380-018-0287-y |
FAROKHNIA MSCHWANDT MLLEE MR ET AL.: "Biobehavioral effects of baclofen in anxious alcohol-dependent individuals: a randomized, double-blind, placebo-controlled, laboratory study", TRANSL PSYCHIATRY, vol. 7, no. 4, 2017, pages 108 |
FILIP, M., FRANKOWSKA, M., PRZEGALINSKI, E.: "Effects of GABAB receptor antagonist, agonists and allosteric positive modulator on the ***e-induced self-administration and drug discrimination", EUR. J. PHARMACOL., vol. 574, 2007, pages 148 - 157, XP022302844, DOI: 10.1016/j.ejphar.2007.07.048 |
FILIP, M., FRANKOWSKA, M., SADAKIERSKA-CHUDY, A., SUDER, A., SZUMIEC, L., MIERZEJEWSKI, P BIENKOWSKI, P., PRZEGALINSKI, E., CRYAN,: "GABA receptors as a therapeutic strategy in substance use disorders: Focus on positive allosteric modulators", NEUROPHARMACOLOGY, vol. 88, 2015, pages 36 - 47 |
FOERSTER BRPETROU MEDDEN RA ET AL.: "Reduced insular γ-aminobutyric acid in fibromyalgia", ARTHRITIS RHEUM, vol. 64, no. 2, 2012, pages 579 - 583 |
FUJIWARA, A., IINO, M., SASAKI, M.: "Relationship between the dose to produce reinforcing effect and that of gross behavioral effects in rhesus monkeys", J. DRUG ABUSE, vol. 2, no. 2, 2016, pages 1 - 9 |
GHOSHOONI, HNOROOZZADEH, AESFANDIARI, BSALIMI, S.H: "GABA receptors within the ventral tegmental area are involved in the expression and acquisition of morphine-induced place preference in morphine-sensitized rats", PHARMACOL. BIOCHEM., vol. 91, 2009, pages 409 - 416, XP025798903, DOI: 10.1016/j.pbb.2008.08.015 |
HAILE CNCARPER BANOLEN TL ET AL.: "The GABAB receptor positive allosteric modulator ASP8062 reduces operant alcohol self-administration in male and female Sprague Dawley rats", PSYCHOPHARMACOLOGY (BERT, 7 July 2021 (2021-07-07) |
HOLAJOVA MFRANEK M: "Effect of short- and long-term administration of baclofen on spatial learning and memory in rats", PHYSIOL RES, vol. 67, no. 1, 2018, pages 133 - 141 |
IIZUKA, HSASAKI, KODAGIRI, NOBO, MIMAIZUMI, MATAI, H: "Measurement of respiratory function using whole-body plethysmography in unanesthetized and unrestrained nonhuman primates", J. TOXICOL. SCI, vol. 35, 2010, pages 863 - 870 |
KATZ DALOCKE CLIU W ET AL.: "Single-Dose Interaction Study of the Arginine Vasopressin Type 1B Receptor Antagonist ABT-436 and Alcohol in Moderate Alcohol Drinkers", ALCOHOL CLIN EXP RES, vol. 40, no. 4, 2016, pages 838 - 845 |
LEGGIO LZYWIAK WHMCGEARY JE ET AL.: "A human laboratory pilot study with baclofen in alcoholic individuals", PHARMACOL BIOCHEM BEHAV, vol. 103, no. 4, 2013, pages 784 - 791, XP028968813, DOI: 10.1016/j.pbb.2012.11.013 |
LIANG, J.H., CHEN, F., KRSTEW, E., COWEN, M.S., CARROLL, F.Y., CRAWFORD, D., BEART, P.M.LAWRENCE, A.J.: "The GABA receptor allosteric modulator CGP7930, like baclofen, reduces operant self-administration of ethanol in alcohol-preferring rats", NEUROPHARMACOLOGY, vol. 50, 2006, pages 632 - 639, XP028079599, DOI: 10.1016/j.neuropharm.2005.11.011 |
LOWE SLWONG CJWITCHER J ET AL.: "Safety, tolerability, and pharmacokinetic evaluation of single- and multiple-ascending doses of a novel kappa opioid receptor antagonist LY2456302 and drug interaction with ethanol in healthy subjects", J CLIN PHARMACOL, vol. 54, no. 9, 2014, pages 968 - 978 |
MACCIONI PCOLOMBO G: "Potential of GABA(B) Receptor Positive Allosteric Modulators in the Treatment of Alcohol Use Disorder", CNS DRUGS, vol. 33, no. 2, 2019, pages 107 - 123 |
MACCIONI PFARA FLORRAI I ET AL.: "Suppressing effect of CMPPE, a new positive allosteric modulator of the GABAB receptor, on alcohol self-administration and reinstatement of alcohol seeking in rats", ALCOHOL, vol. 75, 2019, pages 79 - 87 |
MATTICK, R.PBREEN, CKIMBER, JDAVOLI, M.: "Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence", COCHRANE DATABASE SYST. REV, vol. 3, 2009, pages CD002209 |
MATTICK, R.PBREEN, CKIMBER, JDAVOLI, M: "Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence", COCHRANE DATABASE SYST. REV, vol. 2, 2014, pages CD002207 |
MAY LTAVLANI VASEXTON PM ET AL.: "Allosteric modulation of G protein-coupled receptors", CURR PHARM DES, vol. 10, no. 17, 2004, pages 2003 - 2013 |
MCINTOSH CCHICK J: "Alcohol and the nervous system", J NEUROL NEUROSURG PSYCHIATRY, vol. 75, 2004, pages 16 - 21 |
MORRISON RL, FEDGCHIN M, SINGH J: "Effect of intranasal esketamine on cognitive functioning in healthy participants: a randomized, double-blind, placebo-controlled study", PSYCHOPHARMACOLOGY (BERL, vol. 235, no. 4, 2018, pages 1107 - 1119, XP036466426, DOI: 10.1007/s00213-018-4828-5 |
MOTOTSUGU ITO, ANNA SPENCE, MARY BETH BLAUWET, NAKYO HEO, RONALD GOLDWATER, PAUL MARUFF,GERARD J MAREK: "A phase 1 study to assess potential interaction between ASP8062 and alcohol in healthy adult subjects", J PSYCHOPHARMACOL, vol. 36, no. 6, 7 January 2022 (2022-01-07), pages 756 - 767 |
MURAI, N., KONDO, Y., AKUZAWA, S., MIHARA, T., SHIRAISHI, N., KAKIMOTO, S., MATSUMOTO, M.: "A novel GABA receptor positive allosteric modulator, ASP8062, exerts analgesic effects in a rat model of fibromyalgia", EUR. J. PHARMACOL., vol. 865, 2019, pages 172750, XP055912842, DOI: 10.1016/j.ejphar.2019.172750 |
OLSEN R: "American College of Neuropsychopharmacology", 2002, LIPPINCOTT, WILLIAMS, & WILKINS, article "Neuropsychopharmacology: The Fifth Generation of Progress", pages: 159 - 167 |
PIERCE MSUTTERLAND ABERAHA EM ET AL.: "Efficacy, tolerability, and safety of low-dose and high-dose baclofen in the treatment of alcohol dependence: A systematic review and meta-analysis", EUR NEUROPSYCHOPHARMACOL, vol. 28, no. 7, 2018, pages 795 - 806 |
PIN JPPREZEAU L: "Allosteric modulators of GABA(B) receptors: mechanism of action and therapeutic perspective", CURR NEUROPHARMACOL, vol. 5, no. 3, 2007, pages 195 - 201 |
RASMUSSEN, K., WHITE, D.A., ACRI, J.B.: "NIDA's medication development priorities in response to the opioid crisis: ten most wanted", NEUROPSYCHOPHARMACOLOGY, vol. 44, 2019, pages 657 - 659, XP036700712, DOI: 10.1038/s41386-018-0292-5 |
SCHWARTZ, R.P., GRYCZYNSKI, J., O'GRADY, K.E., SHARFSTEIN, J.M., WARREN, G., OLSEN, Y.: "Opioid agonist treatments and heroin overdose deaths in Baltimore, Maryland, 1995-2009", AM. J. PUBLIC HEALTH, vol. 10, 2013, pages 917 - 922 |
SHOPTAW, S., YANG, X., ROTHERAM-FULLER, E.J., HSIEH, Y.C.M., KINTAUDI, P.C., CHARUVASTRA, V.C.,LING W: "Randomized placebo-controlled trial of baclofen for ***e dependence: preliminary effects for individuals with chronic patterns of ***e use", J. CLIN. PSYCHIATRY, vol. 64, 2003, pages 1440 - 1448 |
SMITH, M.A.: "Nonhuman animal models of substance use disorders: translational value and utility to basic science", DRUG ALCOHOL DEPEND, vol. 206, 2020, pages 1 - 13 |
SPANGEL, R., WEISS, F.: "The dopamine hypothesis of reward: past and current status", TRENDS NEURSCI, vol. 22, 1999, pages 521 - 527 |
STRANG, J., VOLKOW, N.D., DEGENHARDT, L., HICKMAN, M., JOHNSON, K., KOOB, G.F., MARSHALL,B.D.L., TYNDALL, M., WALSH, S.L: "Opioid use disorder", NAT. REV. DISEASE PRIMERS, vol. 6, 2020, pages 3, XP036983362, DOI: 10.1038/s41572-019-0137-5 |
THAI DDYER JEBENOWITZ NL ET AL.: "Gamma-hydroxybutyrate and ethanol effects and interactions in humans", J CLIN PSYCHOPHARMACOL, vol. 26, no. 5, 2006, pages 524 - 529 |
TSUJI, M., NAKAGAWA, Y., ISHIBASHI, Y., YOSHII, T., TAKASHIMA, T., SHIMADA, M., SUZUKI, T.: "Activation of ventral tegmental GABA receptors inhibits morphine-induced place preference in rats", EUR. J. PHARMACOL., vol. 313, 1996, pages 169 - 173, XP002127044, DOI: 10.1016/0014-2999(96)00642-5 |
VARANI APASO EMOUTINHO LM ET AL.: "Attenuation by baclofen of nicotine rewarding properties and nicotine withdrawal manifestations", PSYCHOPHARMACOLOGY (BERL, vol. 231, no. 15, 2014, pages 3031 - 3040 |
VENGELIENE VTAKAHASHI TTDRAVOLINA OA ET AL.: "Efficacy and side effects of baclofen and the novel GABA(B) receptor positive allosteric modulator CMPPE in animal models for alcohol and ***e addiction", PSYCHOPHARMACOLOGY (BERL, vol. 235, no. 7, 2018, pages 1955 - 1965 |
WALZER, MMAREK, G.JWU, R.SNAGATA, MHAN, D: "Single- and multiple-dose safety, tolerability, and pharmacokinetic profiles of ASP8062: results from 2 phase 1 studies", CLIN. PHARMACOL. DRUG DEVELOPMENT, vol. 9, 2020, pages 297 - 306 |
WALZER, MWU, RAHMAD, MFREEMAN, JZAMMIT, GMAREK, G.J: "A randomized phase 1 single-dose polysomnography study of ASP8062, a GABA receptor positive allosteric modulator", PSYCHOPHARMACOLOGY, 2021 |
XI, Z.X., STEIN, EA.: "Baclofen inhibits heroin self-administration behavior and mesolimbic dopamine release", J. PHARMACOL. EXP. THER., vol. 290, 1999, pages 1369 - 1374 |
YOON, S.S., LEE, B.H., KIM, H.S., CHOI, K.H., YUN, J., JANG, E.Y., SHIM, I., KIM, J.A., KIM,M.R., YANG, C.H.: "Potential roles of GABA receptors in morphine self-administration in rats", NEUROSCI. LETT., vol. 428, 2007, pages 33 - 37, XP022318890, DOI: 10.1016/j.neulet.2007.09.034 |
ZARRINDAST, M.R., MOSA-AHMADI, E.: "Effects of GABAergic system on naloxone-inducedjumping in morphine-dependent mice", EUR. J. PHARMACOL., vol. 381, 1999, pages 129 - 133 |
ZOOROB, RALICIA, KGRUBB, AMEJIA, M.: "Buprenorphine therapy for opioid use disorder", AM. FAM. PHYSICIAN, vol. 97, 2018, pages 313 - 320 |
Also Published As
Publication number | Publication date |
---|---|
WO2023028519A3 (en) | 2023-04-20 |
TW202327616A (en) | 2023-07-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Fudala et al. | Effects of buprenorphine and naloxone in morphine-stabilized opioid addicts | |
Schuh et al. | Pharmacokinetic comparison of the buprenorphine sublingual liquid and tablet | |
Johnson et al. | Buprenorphine: considerations for pain management | |
JP4097285B2 (en) | Compositions useful in the manufacture of a medicament for the treatment of various stubborn diseases | |
US20080255097A1 (en) | Methods for the Treatment of Substance Abuse and Dependence | |
KR20130041296A (en) | Pharmaceutical composition comprising dextromethorphan and quinidine for the treatment of neurological disorders | |
JP2016020385A (en) | Methods and compositions for reduction of side effects of therapeutic treatments | |
Zhu et al. | Methylphenidate and μ opioid receptor interactions: a pharmacological target for prevention of stimulant abuse | |
MXPA02006237A (en) | Use of dextromethorphan and oxidase inhibitor for weaning patients from narcotics and antidepressants. | |
Testa et al. | Psychiatric emergencies (part II): psychiatric disorders coexisting with organic diseases. | |
EP2571360A1 (en) | Methods and formulations for oxytocin treatment of substance use, psychiatric and other disorders | |
Gelenberg et al. | Psychoses | |
Akuzawa et al. | Effect of ASP8062 on morphine self-administration and morphine-induced respiratory suppression in monkeys | |
WO2023028519A2 (en) | Methods of treating substance use disorder | |
US20190275048A1 (en) | Method of treating insomnia | |
US20190321341A1 (en) | Use of gaboxadol in the treatment of substance use disorders | |
US20170173039A1 (en) | Compositions and methods to treat addiction | |
JP2005306882A (en) | Composition useful for preparation of medicine for treating emotional instability | |
WO2020089897A1 (en) | Combination of m-opioid receptor (mor) modulators for preventing and treating pain, suicidality and mental disorders | |
Klifto et al. | Pain management in burn patients: pharmacologic management of acute and chronic pain | |
KR20200022026A (en) | Methods of treatment and their forms | |
Hayley | The Psychobiological Implications of Ketamine Misuse | |
ELIE et al. | Comparative hypnotic activity of single doses of loprazolam, flurazepam, and placebo | |
Satterly et al. | Development of a Precision Olfactory Delivery (POD®)-Olanzapine Drug-Device Product for Agitation | |
Ramadan et al. | Response to SSRI-induced enuresis: a case report |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 22777139 Country of ref document: EP Kind code of ref document: A2 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |