JP7079735B2 - 肝内胆汁うっ滞性疾患の処置 - Google Patents
肝内胆汁うっ滞性疾患の処置 Download PDFInfo
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- JP7079735B2 JP7079735B2 JP2018562567A JP2018562567A JP7079735B2 JP 7079735 B2 JP7079735 B2 JP 7079735B2 JP 2018562567 A JP2018562567 A JP 2018562567A JP 2018562567 A JP2018562567 A JP 2018562567A JP 7079735 B2 JP7079735 B2 JP 7079735B2
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Classifications
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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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
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- Veterinary Medicine (AREA)
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- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Physiology (AREA)
- Nutrition Science (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Farming Of Fish And Shellfish (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
胆汁うっ滞は、肝臓から十二指腸までの胆汁の流れが遅くなるかまたは遮断される状態である。胆汁うっ滞は、便宜上2つのタイプに分けられ得る:胆汁形成が様々な疾患、長期静脈栄養などの状態により、または特定の薬物(例えば一部の抗生物質)の副作用として妨げられる、肝臓内部のものである、肝内胆汁うっ滞;および典型的に胆汁の流れが胆管の機械的な一部もしくは完全な閉鎖、例えば胆管腫瘍、包嚢、胆管結石、狭窄または胆管への圧力により妨げられる、肝臓外部で生じる、肝外胆汁うっ滞;ただし、原発性硬化性胆管炎(PSC)は肝内または肝外であり得る。胆汁うっ滞の一般的症状は、疲労感、掻痒(かゆみ)、黄疸および黄色腫(コレステロールの豊富な物質の皮膚下の沈着)を含む。胆汁うっ滞の影響は、深刻で広範囲であり、全身疾患、肝不全および肝移植の必要性を伴う肝疾患の悪化につながる。
上述のように、UDCAは、胆汁うっ滞を軽減し、肝機能を改善する作用のため、肝内胆汁うっ滞性疾患の一般的処置である。しかしながら、2012年のPBCにおけるUDCAのコクランレビューでは、UDCAは、肝臓病理、黄疸および腹水のバイオマーカーの減少を示したが、死亡率または肝移植に対するUDCAのベネフィットについて医学文献にエビデンスはなく、一方その使用は体重増加およびコストを伴ったことが見出された。
セラデルパル(推奨INN)は、式
「肝内胆汁うっ滞性疾患」およびその処置は、[背景技術]の「肝内胆汁うっ滞性疾患」および「肝内胆汁うっ滞性疾患の処置」と題したサブセクションに記載される。
(1)肝内胆汁うっ滞性疾患を発症する危険性を防止するかまたは減少させること、すなわち、肝内胆汁うっ滞性疾患に罹患しやすいかもしれないが、肝内胆汁うっ滞性疾患の症状をまだ経験していないかまたは呈していない対象体において肝内胆汁うっ滞性疾患の臨床症状を発症しないようにすること(すなわち予防);
(2)肝内胆汁うっ滞性疾患を抑制すること、すなわち、肝内胆汁うっ滞性疾患またはその臨床症状の発症を妨げるかまたは軽減すること;ならびに
(3)肝内胆汁うっ滞性疾患を緩和すること、すなわち、肝内胆汁うっ滞性疾患の退行、回復または改善を引き起こすか、またはその臨床症状の数、頻度、持続もしくは重症度を減少させること。
セラデルパルは、処置される対象体および対象体の状態の性質に適する任意の経路によって投与され得る。投与経路は、静脈内、腹腔内、筋肉内および皮下注射を含む注射による投与、経粘膜または経皮送達による投与、局所適用、経鼻スプレー、坐剤などによる投与を含み、あるいは経口投与されてもよい。製剤は、所望により、リポソーム製剤、エマルジョン、粘膜を介して薬物を投与するよう設計された製剤、または経皮製剤であり得る。これらの投与方法各々に適する製剤は、例えば"Remington: The Science and Practice of Pharmacy", 20版, Gennaro編, Lippincott Williams & Wilkins, Philadelphia, Pa., U.S.A.で見出すことができる。セラデルパルが経口的に利用可能であるため、典型的な製剤は経口であり、典型的な剤形は、経口投与用の錠剤またはカプセル剤になる。「セラデルパル」のサブセクションで述べたように、セラデルパルは、臨床試験のためにカプセル剤に製剤化されている。
試験対象体は、下記の3つの基準のうち少なくとも2つによりPBCと診断された男性または女性の成人である:(a)少なくとも6ヵ月間、アルカリホスファターゼ(ALP)が正常値上限(ULN)を超える既往歴、(b)免疫蛍光法において陽性抗ミトコンドリア抗体価>1/40、または酵素結合免疫吸着法によりM2陽性、または陽性PBC特異的抗核抗体、ならびに(c)PBCに一致する肝生検の結果、過去12ヵ月間の安定かつ推奨される用量のUDCAおよびALP≧1.67×ULN。除外基準には、ASTまたはALT≧3×ULN、総ビリルビン(TBIL)≧2×ULN、自己免疫性肝炎または慢性ウイルス性肝炎の既往歴、PSC、フィブラートまたはシンバスタチンの現在の使用、コルヒチン、メトトレキサート、アザチオプリンまたは合成ステロイドの過去2ヶ月における使用、PBCに対する実験的処置の使用、および実験的または未承認の免疫抑制剤の使用が含まれる。主要な試験評価項目は、ALPの減少であり、副次評価項目は、ALP<1.67×ULNおよび正常範囲内の総ビリルビンを達成する対象体のレスポンダー割合、およびALPの>15%減少であった。更なる副次評価項目は、GGT、TBILおよび5'-ヌクレオチダーゼの変化であり、これは胆汁うっ滞の他の認識されている生化学マーカーである。対象体は、プラセボ、50 mg/日または200 mg/日のセラデルパルいずれかが12週間経口投与されるよう無作為に割付けられた。試験中に、トランスアミナーゼの無症候性の増加が3例観察された(200 mg群において2例および50 mg群において1例)。3例すべて処置中断で可逆的であり、TBILの増加を伴わなかった。試験が明らかな有効性シグナルをすでに示していたので、試験を中止した。試験を非盲検化した後、試験に登録され少なくとも2週間の処置を完了した26名の対象体(プラセボ群で10名、50 mg/日セラデルパル群で9名、200 mg/日セラデルパル群で7名)の利用可能なデータを用いて、主要評価項目ALPの変化を分析した。当初の統計計画に従って、last observation carried forward(LOCF)を用いてALPの変化を計算した。ALPのベースラインからの平均減少は、50 mg/日および200 mg/日投与群についてはそれぞれ57%および62%であり、これに対してプラセボでは0.37%であった(両方についてp<0.0001)。プラセボ、50 mg/日および200 mg/日群のレスポンダー割合は、ベースラインALPレベルが239、313および280 U/Lで異なるにもかかわらず、それぞれ10%、67%および100%であった。50 mg/日および200 mg/日群のレスポンダー割合をプラセボと比較するp値は、それぞれ0.020および0.0004(フィッシャーの正確確率検定)であった。したがって、セラデルパルは、PBCの対象体において急速で強力な胆汁うっ滞抑制作用を示した。用量反応がないことは、低用量でも同様に有効であることを示唆する。セラデルパルでの最近完了した前臨床試験では、該薬物の主な***経路は胆汁によるものであり、薬物は胆汁中に濃縮されることが示され、またPBCの対象体は胆汁の流れが障害されているため、PBCの対象体における肝臓への薬物の曝露は、正常な肝機能を有する対象体における以前の臨床試験におけるものより高くなり得て、これは、より強力な胆汁うっ滞抑制作用およびトランスアミナーゼ作用の両方を説明する。セラデルパルを投与される対象体はまた、投与2週間後、プラセボの0.8%に対して50 mg/日および200 mg/日投与群ではそれぞれ16%および26%のLDL-Cの減少を含む代謝パラメーターの改善を示した。強力な胆汁うっ滞抑制作用にもかかわらず、掻痒の有害事象が処置において報告されなかったこともまた注目すべきである。
PBCなどの肝内胆汁うっ滞性疾患を有する成人対象体を、5、10、25または50 mg/日のセラデルパルの経口投与で処置する。対象体は、UDCAを含む通常の他の医薬が許される。試験前、試験中一定間隔、例えば試験中4週間ごと、およびセラデルパル治療の最後の投与の4週間後に、安全性および薬力学的評価のために、対象体を評価する。各来院時に、12時間絶食後、血液および尿を採取し;標準的な代謝パネル、全血球計算および標準的な尿検査を実施する。血液を、TC、HDL-C、TG、VLDL-C、LDL-Cおよびアポリポタンパク質Bについて、肝機能マーカー、例えば総および骨特異的アルカリホスファターゼについて、γ-グルタミルトランスペプチダーゼについて、ならびに総および抱合型ビリルビンについて分析する。対象体はまた健康日記を継続し、これは各来院時にレビューされる。対象体は、例えばALPおよびGGTの減少によって示されるように、疾患の改善を示す。
Claims (7)
- 原発性胆汁性胆管炎の処置のための、経口投与用の医薬であって、セラデルパル(Seladelpar)またはその塩である化合物を、5mg/日または10mg/日のセラデルパルに相当する量で含む、医薬。
- 前記化合物が、セラデルパルのL-リシン塩である、請求項1に記載の医薬。
- 前記化合物が、セラデルパルL-リシン二水和物である、請求項2に記載の医薬。
- 1日1回投与である、請求項1~3のいずれか一項に記載の医薬。
- 前記化合物の量が、5mg/日のセラデルパルに相当する量である、請求項4に記載の医薬。
- 前記化合物の量が、10mg/日のセラデルパルに相当する量である、請求項4に記載の医薬。
- 錠剤またはカプセル剤である、請求項1~6のいずれか一項に記載の医薬。
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