JP2012025756A - 選択的s1p1レセプターアゴニストの投与法 - Google Patents
選択的s1p1レセプターアゴニストの投与法 Download PDFInfo
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Abstract
【解決手段】初期治療期の間においては、選択的S1P1レセプターアゴニストを、心臓の脱感作を惹起する用量、かつ心臓の脱感作を維持する投与頻度にて、さらなる急性の心拍数減少が起こらなくなるまで投与し、当該用量は標的用量未満であり、続いて選択的S1P1レセプターアゴニストの標的用量への用量漸増を行うように、選択的S1P1レセプターアゴニストを対象に投与する、選択的S1P1レセプターアゴニストの投与法。
【選択図】なし
Description
化合物、(R)−5−[3−クロロ−4−(2,3−ジヒドロキシ−プロポキシ)−ベンズ[Z]イリデン]−2−([Z]−プロピルイミノ)−3−o−トリル−チアゾリジン−4−オン((R)−5−[3−chloro−4−(2,3−dihydroxy−propoxy)−benz[Z]ylidene]−2−([Z]−propylimino)−3−o−tolyl−thiazolidin−4−one)(以下、「化合物1」とも記載する。;化合物1の製造及びその医薬としての使用は、公開されたPCT出願、WO2005/054215に記載されている。)は、選択的S1P1レセプターアゴニストであり、そしてヒトに対し、5mg以上の用量を毎日繰り返して経口投与すると、末梢血リンパ球数の、一貫的、持続的かつ用量依存的減少を招く。しかしながら、驚くべきことに、選択的S1P1レセプターアゴニストである化合物1が、ヒトにおいて、一時的に心拍を減少させ、その効果は投与後1〜3時間後に最大になることが見出された。いくつかの個体においては、心電図(ECG)におけるPRインターバルの、同様に一時的な増大、及び関連した不規則な心拍(いわゆる、Wenckebachリズム)を伴う。投与後の期間には、倦怠感及びめまいも時折生じる。心拍及びリズム及び倦怠感/めまいに対する化合物1のこれらの急性的な効果は、10mgでは、20mgよりも軽度である。これらの効果のすべては、投与を繰り返すことにより減衰する。すなわち、5〜20mgの用量を2〜4日間、毎日経口投与すると、投与前の値と比較した急性の心拍数減少は、化合物1を投与してももはや観察されない。同様に、5〜20mgの用量の化合物1を毎日繰り返し経口投与すると、投与前の値と比較したECGのPRインターバルの一時的増大は観察されず、倦怠感やめまいも報告されない。心拍、房室伝導に対する効果又は倦怠感若しくはめまいは、深刻な副作用ではないにしても、望ましいものではなく、そしてこれらの効果を最小化する方法は、化合物1及び他の選択的S1P1レセプターアゴニストの許容性(tolerability)及び安全性を最大化し、そして投与開始の初期又は、断薬後の薬剤療法再開時の関連するモニターの必要性を最小化する上で価値あるものである。
態様i)に従う投与のための、選択的S1P1レセプターアゴニストの異なる薬剤ユニットを含むキットであって、当該選択的S1P1レセプターアゴニストの標的用量未満の用量強度の1又は2以上のユニットが初期治療期用に提供され、そして当該選択的S1P1レセプターアゴニストの標的用量までのより高い用量強度の後続の薬剤ユニットが提供される、当該キットに関する。
本明細書で使用する「心臓の脱感作」という用語は、薬剤投与後の急性の心拍数減少の欠如を意味する。
Claims (10)
- (R)−5−[3−クロロ−4−(2,3−ジヒドロキシ−プロポキシ)−ベンズ[Z]イリデン]−2−([Z]−プロピルイミノ)−3−o−トリル−チアゾリジン−4−オン(化合物1)又はその薬学的に許容される塩を有効成分として含有し、前記化合物1又はその薬学的に許容される塩が対象へ、初期治療期の間において、経口で、標的用量未満である5−20mgが1日1回少なくとも2日間投与され、続いて経口で、1日1回少なくとも20mg投与される量である前記標的用量への用量漸増を1回又は数回の用量増大で行うように投与される、選択的S1P1レセプターアゴニスト薬。
- 前記化合物1又はその薬学的に許容される塩が、初期治療期の間において、経口で、5−10mgが1日1回少なくとも2日間投与され、続いて経口で1日1回少なくとも20mg投与される量である前記標的用量への用量漸増を1回又は数回の用量増大で行うように投与される、請求項1に記載の選択的S1P1レセプターアゴニスト薬。
- (R)−5−[3−クロロ−4−(2,3−ジヒドロキシ−プロポキシ)−ベンズ[Z]イリデン]−2−([Z]−プロピルイミノ)−3−o−トリル−チアゾリジン−4−オン(化合物1)又はその薬学的に許容される塩を有効成分として含有し、請求項1又は2に記載の投与が行われ、前記標的用量が経口で1日1回20−40mg投与される量である、選択的S1P1レセプターアゴニスト薬。
- (R)−5−[3−クロロ−4−(2,3−ジヒドロキシ−プロポキシ)−ベンズ[Z]イリデン]−2−([Z]−プロピルイミノ)−3−o−トリル−チアゾリジン−4−オン(化合物1)又はその薬学的に許容される塩を有効成分として含有し、請求項1ないし3のいずれか1項に記載の投与が行われ、前記初期治療期の間において、前記化合物1又はその薬学的に許容される塩が、2−4日間投与される、選択的S1P1レセプターアゴニスト薬。
- (R)−5−[3−クロロ−4−(2,3−ジヒドロキシ−プロポキシ)−ベンズ[Z]イリデン]−2−([Z]−プロピルイミノ)−3−o−トリル−チアゾリジン−4−オン(化合物1)又はその薬学的に許容される塩を有効成分として含有し、請求項1ないし3のいずれか1項に記載の投与が行われ、前記初期治療期の間において、前記化合物1又はその薬学的に許容される塩が、少なくとも4日間投与される、選択的S1P1レセプターアゴニスト薬。
- (R)−5−[3−クロロ−4−(2,3−ジヒドロキシ−プロポキシ)−ベンズ[Z]イリデン]−2−([Z]−プロピルイミノ)−3−o−トリル−チアゾリジン−4−オン(化合物1)又はその薬学的に許容される塩が、初期治療期の間において、経口で5mgが1日1回3日間投与され、続いて経口で1日1回3日間、10mgへの用量漸増を行うように投与され、続いて経口で1日1回20mg投与される量である前記標的用量への用量漸増を行うように投与される、請求項1ないし4のいずれか1項に記載の選択的S1P1レセプターアゴニスト薬。
- (R)−5−[3−クロロ−4−(2,3−ジヒドロキシ−プロポキシ)−ベンズ[Z]イリデン]−2−([Z]−プロピルイミノ)−3−o−トリル−チアゾリジン−4−オン(化合物1)又はその薬学的に許容される塩を有効成分として含有し、請求項1ないし6のいずれか1項に記載の投与が行われ、活性化された免疫系と関連する疾患若しくは障害の予防及び/又は治療に用いられる、選択的S1P1レセプターアゴニスト薬。
- (R)−5−[3−クロロ−4−(2,3−ジヒドロキシ−プロポキシ)−ベンズ[Z]イリデン]−2−([Z]−プロピルイミノ)−3−o−トリル−チアゾリジン−4−オン(化合物1)又はその薬学的に許容される塩を有効成分として含有し、請求項1ないし6のいずれか1項に記載の投与が行われ、腎臓、肝臓、心臓、肺、膵臓、角膜及び皮膚等の移植された臓器に対する拒絶反応;幹細胞移植によりもたらされる移植片対宿主病;関節リウマチ、多発性硬化症、クローン病及び潰瘍性大腸炎等の炎症性腸疾患、乾癬、乾癬性関節炎、橋本甲状腺炎等の甲状腺炎、及びブドウ膜網膜炎を含む自己免疫症候群;鼻炎、結膜炎及び皮膚炎等のアトピー性疾患;喘息;I型糖尿病;リウマチ熱及び感染後糸球体腎炎を含む感染後自己免疫疾患;固形癌並びに腫瘍転移、からなる群より選択される疾患若しくは障害の予防及び/又は治療に用いられる、選択的S1P1レセプターアゴニスト薬。
- (R)−5−[3−クロロ−4−(2,3−ジヒドロキシ−プロポキシ)−ベンズ[Z]イリデン]−2−([Z]−プロピルイミノ)−3−o−トリル−チアゾリジン−4−オン(化合物1)又はその薬学的に許容される塩を有効成分として含有し、請求項1ないし6のいずれか1項に記載の投与が行われ、腎臓、肝臓、心臓及び肺から選択される移植された臓器に対する拒絶反応;幹細胞移植によりもたらされる移植片対宿主病;関節リウマチ、多発性硬化症、乾癬、乾癬性関節炎、クローン病及び橋本甲状腺炎から選択される自己免疫症候群;及びアトピー性皮膚炎からなる群より選択される疾患若しくは障害の予防及び/又は治療に用いられる、選択的S1P1レセプターアゴニスト薬。
- (R)−5−[3−クロロ−4−(2,3−ジヒドロキシ−プロポキシ)−ベンズ[Z]イリデン]−2−([Z]−プロピルイミノ)−3−o−トリル−チアゾリジン−4−オン(化合物1)又はその薬学的に許容される塩を有効成分として含有し、請求項1ないし6のいずれか1項に記載の投与が行われ、多発性硬化症及び乾癬から選択される疾患若しくは障害の予防及び/又は治療に用いられる、選択的S1P1レセプターアゴニスト薬。
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JP5416600B2 (ja) | 2010-01-22 | 2014-02-12 | 株式会社日立ハイテクノロジーズ | 欠陥検査装置およびその方法 |
DK2885266T3 (da) | 2012-08-17 | 2020-06-08 | Actelion Pharmaceuticals Ltd | Fremgangsmåde til fremstilling af (2z,5z)-5-(3-chlor-4-((r)-2,3-dihydroxypropoxy)benzyliden)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-on og mellemprodukt, der anvendes i fremgangsmåden |
US10220023B2 (en) | 2014-12-11 | 2019-03-05 | Actelion Pharmaceuticals Ltd | Dosing regimen for a selective S1P1 receptor agonist |
MA41139A (fr) | 2014-12-11 | 2017-10-17 | Actelion Pharmaceuticals Ltd | Combinaison pharmaceutique comportant un agoniste sélectif du récepteur sip1 |
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JP2005535679A (ja) * | 2002-07-24 | 2005-11-24 | ノバルティス アクチエンゲゼルシャフト | 心臓疾患におけるs1pレセプターアゴニストの使用 |
JP2007511563A (ja) * | 2003-11-21 | 2007-05-10 | アクテリオン ファマシューティカルズ リミテッド | 新規チアゾリジン−4−オン誘導体 |
WO2009115954A1 (en) * | 2008-03-17 | 2009-09-24 | Actelion Pharmaceuticals Ltd | Dosing regimen for a selective s1p1 receptor agonist |
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