WO2023028519A2 - Methods of treating substance use disorder - Google Patents

Methods of treating substance use disorder Download PDF

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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
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Prior art keywords
patient
use disorder
treating
compound
pharmaceutically acceptable
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PCT/US2022/075393
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French (fr)
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WO2023028519A3 (en
Inventor
Paul BLAHUNKA
Gerard MAREK
Mototsugu Ito
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Astellas Pharma Global Development, Inc.
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Application filed by Astellas Pharma Global Development, Inc. filed Critical Astellas Pharma Global Development, Inc.
Publication of WO2023028519A2 publication Critical patent/WO2023028519A2/en
Publication of WO2023028519A3 publication Critical patent/WO2023028519A3/en

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    • 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.

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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):
Figure imgf000004_0001
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):
Figure imgf000013_0001
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) is the compound having the following structure:
Figure imgf000020_0001
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.
Figure imgf000077_0001
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:
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000079_0002
Figure imgf000080_0001
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)
Figure imgf000085_0001
Vehicle: 0.5% MC
B.A. : Before adtesistration
* : The value represents the mean value of the date of the animal No. 1 and 2.
Table 2 Respiratory parameters (Tidal volume)
Figure imgf000086_0001
Vehicle: 0 5% MC
B.A.: Before administration
*: The value represents the mean value of she data of the animal No. 1 and 2.
Table 3 Respiratory parameters (Minnie volume)
Figure imgf000087_0001
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
Plasma Concentrations of ASP8062 alter a Single Oral Administration ef ASP8062 to monkeys
Figure imgf000088_0001
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 1. Demographic and Baseline Characteristics by Sequence
Figure imgf000107_0001
Figure imgf000108_0001
Example 3 Table 2. Plasma Pharmacokinetic Parameters of ASP8062 After Administration Alone and in the Presence of Alcohol (Pharmacokinetic Analysis Set, Excluding 1 Outlier)
Figure imgf000108_0002
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
Figure imgf000109_0001
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
Figure imgf000109_0002
Figure imgf000110_0001
Abbreviations: CI, confidence interval; LS, least squares.
Example 3 Table 5. Postural Stability Statistical Assessment of Pharmacodynamic Interaction Between ASP8062 and Alcohol
Figure imgf000110_0002
Abbreviations: CI, confidence interval; LS, least squares.
Example 3 Table 6. Postural Stability Statistical Assessment of Potentiation Effect of ASP8062 in Combination with Alcohol
Figure imgf000110_0003
Abbreviations: CI, confidence interval; LS, least squares.
Example 3 Table 7. Incidence of Treatment-Related Adverse Events
Figure imgf000110_0004
Example 3 Table SI. Plasma Pharmacokinetic Profile of ASP8062 Alone or in Combination with Alcohol for Complete Subject Data Set
Figure imgf000111_0001
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
Figure imgf000111_0002
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
Figure imgf000112_0001
Abbreviations: CI, confidence interval; LS, least squares. Example 3 Table S4. Cogstate Battery Statistical Assessment of Potential Pharmacodynamic Effect of Alcohol
Figure imgf000112_0002
Abbreviations: CI, confidence interval; LS, least squares.
Example 3 Table S5. Postural Stability Statistical Assessment of Potential Pharmacodynamic Effect of ASP8062 and Alcohol
Figure imgf000112_0003
Figure imgf000113_0001
Abbreviations: CI, confidence interval; LS, least squares.
Example 3 Table S6. C-SSRS Categorized Results of ASP8062 and Alcohol (Safety Analysis Set)
Figure imgf000113_0002
Abbreviation: C-SSRS, Columbia-Suicide Severity Rating Scale.
Example 3 Table S7. Percent Blood Oxygen Saturation by Treatment Condition
Figure imgf000113_0003
Abbreviation: SD, standard deviation.
Example 3 Table S8. Bond-Lader VAS Domain Results of ASP8062 and Alcohol (Safety Analysis Set)
Figure imgf000113_0004
Calmness m
Figure imgf000114_0001
Abbreviations: SD, standard deviation; VAS, Visual Analogue Scale.
Example 3 Table S9. ARCI-49 Questionnaire Subscale Scores for ASP8062 and Alcohol (Safety Analysis Set)
Figure imgf000114_0002
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)
Figure imgf000114_0003
*n=19.
Abbreviation: SD, standard deviation. Example 3 Table Sil. Drug Effects Questionnaire Scores for ASP8062 and Alcohol (Safety Analysis Set)
Figure imgf000115_0001
Example 3 Table S12. Daytime Somnolence Scale Ratings Results for ASP8062 and Alcohol (Safety Analysis Set)
Figure imgf000115_0002
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.
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
INCORPORATION BY REFERENCE
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.
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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.
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