JP7397011B2 - S1p1受容体に関連する状態を治療する方法 - Google Patents
S1p1受容体に関連する状態を治療する方法 Download PDFInfo
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Description
ヒト肝ミクロソームにおけるシトクロムP450(CYP)およびUDP-グルクロノシルトランスフェラーゼ(UGT)酵素の阻害剤としての化合物1のインビトロ評価
化合物1は、同時投与される薬物の代謝を阻害する化合物1の潜在能力を確認することを目的として、ヒト肝ミクロソームにおけるシトクロムP450(CYP)酵素CYP1A2、CYP2B6、CYP2C8、CYP2C9、CYP2C19、CYP2D6、CYP3A4/5(2つの異なるマーカー基質を使用)ならびにUDP-グルクロノシルトランスフェラーゼ(UGT)酵素UGT1A1、UGT1A3、UGT1A4、UGT1A6、UGT1A9、UGT2B7、およびUGT2B17の潜在的な阻害について評価した。
化合物1は、ヒトABC輸送体P-gp、BCRP、およびBSEPまたはヒトSLC輸送体OATP1B1、OATP1B3、OAT1、OAT3、OCT1、OCT2、MATE1、およびMATE2-Kの潜在的な基質および/または阻害剤として評価した。P-gpおよびBCRPは、多くの組織の頂端膜に発現する。P-gpおよびBCRPは、腸細胞の管腔膜、脳の内皮細胞、腎近位尿細管の刷子縁膜、および肝細胞の小管膜で発現し、腸吸収、血液-脳関門浸透を制限し、胆汁および尿への排泄を促進する。BSEPは、主に肝細胞の小管膜で発現し、胆汁への排泄を促進する。OATP1B1、OATP1B3、およびOCT1は、肝細胞の類洞膜で発現し、さらなる代謝または胆汁への排泄のために内因性および生体異物化合物の肝細胞への蓄積を促進する。OAT1、OAT3、およびOCT2は、腎近位尿細管の側底膜で発現し、尿へのさらなる排泄のために近位尿細管への化合物の蓄積を促進する。MATE1およびMATE2-K(多剤および毒素排出タンパク質)は、主に近位尿細管細胞の管腔(頂端)膜で発現し、カチオンおよび双性イオンの尿への排泄において役割を果たすと考えられている。MATE1はまた、肝臓において肝細胞の小管膜で発現し、カチオン性薬物の胆汁中排泄を媒介する。MATE1およびMATE2-Kは、肝細胞の小管膜および近位尿細管の側底膜で発現するOCT輸送体と連携して機能して、排泄を媒介し得る。輸送体の基質または阻害剤である化合物は、薬物間相互作用の被害者または加害者であり得る。
化合物1は、評価された条件下、P-gp、BCRP、OATP1B1、OATP1B3、OAT1、OAT3、OCT1、およびOCT2輸送体の基質ではなかった。化合物1は、それぞれ、約100、35.7、および約10μMのIC50値で、P-gp、BCRP、およびOATP1B1を阻害した。化合物1(最大10μM)は、調査された全ての他の輸送体(BSEP、OATP1B3、OAT1、OAT3、OCT1、OCT2、MATE1、およびMATE2-K)の50%未満の阻害を引き起こした。
化合物1を評価して、絶食状態での2mgの錠剤およびカプセル製剤の単回用量相対経口バイオアベイラビリティを評価し、2mgの錠剤の薬物動態に対する食品の効果を決定し、化合物1薬物動態における潜在的な性差を評価し、健康な成人対象における安全性および耐容性を評価した。
化合物1(1mg、2mg)は、健康な成人対象においてフルコナゾール(CYP2C9の中程度の阻害剤)、ゲムフィブロジル(CYP2C8の強力な阻害剤)、またはリファンピン(CYP2C8およびCYP2C9の両方の中程度の誘導剤)の投与の存在および不在下で血漿薬物動態(PK)、薬力学(PD)、安全性、および耐容性を評価するために、非盲検、3つの治療、ランダム化、固定シーケンス試験において評価される。
Cmax:濃度時間プロファイルから直接決定された最大濃度
tmax:濃度-時間プロファイルから直接決定された薬物投与後に最大血漿濃度に達するまでの時間
t1/2:ln2/λzとして計算された終末排出半減期
λz:濃度-時間曲線の終末相での少なくとも3つのデータ点の選択によって決定された終末排出速度定数
AUC0-24:線形対数台形公式を使用して計算された0~24時間の濃度-時間曲線下面積(AUC)
AUC0-168:線形対数台形公式を使用して計算された0~168時間の濃度-時間曲線下面積(AUC)
AUC0-t
AUClast:線形対数台形公式を使用して計算された時間ゼロから最後の定量可能な濃度(tlast)の時間までのAUC
AUC0-∞:線形対数台形公式を使用して計算された時間ゼロから無限大までのAUC
CL/F:経口投与後の全身クリアランス
Vz/F:終末相に基づく経口投与後の見かけの分布容積
MR:AUC0-168(代謝産物)/AUC0-168(親)として計算された代謝比
本発明のまた別の態様は、以下のとおりであってもよい。
〔1〕スフィンゴシン1-リン酸サブタイプ1(S1P 1 )受容体関連障害を有する個体を治療する方法であって、
それを必要とする前記個体に、治療有効量の(R)-2-(7-(4-シクロペンチル-3-(トリフルオロメチル)ベンジルオキシ)-1,2,3,4-テトラヒドロシクロペンタ[b]インドール-3-イル)酢酸(化合物1)、またはその薬学的に許容される塩、水和物、もしくは溶媒和物を含む薬学的投与剤を投与することを含み、
前記薬学的投与剤が、約0.8~約1.25の血漿濃度対時間曲線下面積の平均摂食/絶食比、および約0.8~約1.25の最大血漿濃度(Cmax)の平均摂食/絶食比を有する、方法。
〔2〕(R)-2-(7-(4-シクロペンチル-3-(トリフルオロメチル)ベンジルオキシ)-1,2,3,4-テトラヒドロシクロペンタ[b]インドール-3-イル)酢酸(化合物1)、またはその薬学的に許容される塩、水和物、もしくは溶媒和物から選択されるスフィンゴシン1-リン酸サブタイプ1(S1P 1 )受容体調節剤を、それを必要とする患者に投与する方法であって、前記患者が、シトクロムP450(CYP)基質、有機アニオン輸送体(OAT)基質、UDP-グルクロノシルトランスフェラーゼ(UGT)基質、シトクロムP450 2C8(CYP2C8)阻害剤、シトクロムP450 2C9(CYP2C9)阻害剤、CYP2C8誘導剤、CYP2C9誘導剤、UDP-グルクロノシルトランスフェラーゼ(UGT)酵素UGT1A1阻害剤、またはUDP-グルクロノシルトランスフェラーゼ(UGT)酵素UGT1A6阻害剤も投与されており、
前記患者に治療有効量の前記S1P 1 調節剤を投与することを含み、
前記S1P 1 調節剤の前記治療有効量が、CYP基質、OAT基質、UGT基質、CYP2C8阻害剤、CYP2C9阻害剤、CYP2C8誘導剤、CYP2C9誘導剤、UGT1A1阻害剤、またはUGT1A6阻害剤を投与されていない患者に投与される量より少ない、方法。
〔3〕(R)-2-(7-(4-シクロペンチル-3-(トリフルオロメチル)ベンジルオキシ)-1,2,3,4-テトラヒドロシクロペンタ[b]インドール-3-イル)酢酸(化合物1)、またはその薬学的に許容される塩、水和物、もしくは溶媒和物から選択されるスフィンゴシン1-リン酸サブタイプ1(S1P 1 )受容体調節剤を、それを必要とする患者に投与する方法であって、
前記患者に治療有効量の前記S1P 1 調節剤を投与することと、
その後前記患者がCYP基質、OAT基質、UGT基質、CYP2C8阻害剤、CYP2C9阻害剤、CYP2C8誘導剤、CYP2C9誘導剤、UDP-グルクロノシルトランスフェラーゼ(UGT)酵素UGT1A1阻害剤、またはUDP-グルクロノシルトランスフェラーゼ(UGT)酵素UGT1A6阻害剤による治療を開始することを決定することと、
前記S1P 1 調節剤を、CYP基質、OAT基質、UGT基質、CYP2C8阻害剤、CYP2C9阻害剤、CYP2C8誘導剤、CYP2C9誘導剤、UDP-グルクロノシルトランスフェラーゼ(UGT)酵素UGT1A1阻害剤、またはUDP-グルクロノシルトランスフェラーゼ(UGT)酵素UGT1A6阻害剤を投与されていない患者に投与される量より少ない量で投与することと、を含む、方法。
〔4〕前記患者または医療従事者に、CYP基質、OAT基質、UGT基質、CYP2C8阻害剤、CYP2C9阻害剤、CYP2C8誘導剤、CYP2C9誘導剤、UDP-グルクロノシルトランスフェラーゼ(UGT)酵素UGT1A1阻害剤、またはUDP-グルクロノシルトランスフェラーゼ(UGT)酵素UGT1A6阻害剤も投与されている患者への前記S1P 1 調節剤の投与が、CYP基質、OAT基質、UGT基質、CYP2C8阻害剤、CYP2C9阻害剤、CYP2C8誘導剤、CYP2C9誘導剤、UDP-グルクロノシルトランスフェラーゼ(UGT)酵素UGT1A1阻害剤、またはUDP-グルクロノシルトランスフェラーゼ(UGT)酵素UGT1A6阻害剤を投与されていない患者への前記S1P 1 調節剤の投与よりも高い前記S1P 1 調節剤の曝露をもたらすことを通知することをさらに含む、前記〔2〕または〔3〕に記載の方法。
〔5〕前記患者または医療従事者に、CYP基質、OAT基質、UGT基質、CYP2C8阻害剤、CYP2C9阻害剤、CYP2C8誘導剤、CYP2C9誘導剤、UDP-グルクロノシルトランスフェラーゼ(UGT)酵素UGT1A1阻害剤、またはUDP-グルクロノシルトランスフェラーゼ(UGT)酵素UGT1A6阻害剤も投与されている患者への前記S1P 1 調節剤の投与が、CYP基質、OAT基質、UGT基質、CYP2C8阻害剤、CYP2C9阻害剤、CYP2C8誘導剤、CYP2C9誘導剤、UDP-グルクロノシルトランスフェラーゼ(UGT)酵素UGT1A1阻害剤、またはUDP-グルクロノシルトランスフェラーゼ(UGT)酵素UGT1A6阻害剤を投与されていない患者への前記S1P 1 調節剤の投与よりも1つ以上の曝露関連有害反応のリスクの増加をもたらし得ることを通知することをさらに含む、前記〔2〕~〔4〕のいずれか一項に記載の方法。
〔6〕(R)-2-(7-(4-シクロペンチル-3-(トリフルオロメチル)ベンジルオキシ)-1,2,3,4-テトラヒドロシクロペンタ[b]インドール-3-イル)酢酸(化合物1)、またはその薬学的に許容される塩、水和物、もしくは溶媒和物から選択されるスフィンゴシン1-リン酸サブタイプ1(S1P 1 )受容体調節剤を、それを必要とする患者に投与する方法であって、前記患者が、膜輸送体の基質も投与されており、前記膜輸送体が、P-糖タンパク質(Pgp)、BCRP(乳癌耐性タンパク質)、およびOATP1B1から選択され、
前記患者に治療有効量の前記S1P 1 調節剤を投与することを含む、方法。
〔7〕前記膜輸送体の前記基質に関連する毒性および臨床応答の徴候および症状について前記患者を監視することをさらに含む、前記〔6〕に記載の方法。
〔8〕前記膜輸送体の前記基質に関する1つ以上の曝露関連有害反応に耐容性である前記患者の能力に基づいて、前記患者に投与される前記膜輸送体の前記基質の量を低減することをさらに含む、前記〔6〕または〔7〕に記載の方法。
〔9〕R)-2-(7-(4-シクロペンチル-3-(トリフルオロメチル)ベンジルオキシ)-1,2,3,4-テトラヒドロシクロペンタ[b]インドール-3-イル)酢酸(化合物1)、またはその薬学的に許容される塩および/もしくは同位体バリアントから選択されるスフィンゴシン1-リン酸サブタイプ1(S1P 1 )受容体調節剤を、それを必要とする患者に投与する方法であって、
前記患者に治療有効量の前記S1P 1 受容体調節剤を投与することと、
その後前記患者が膜輸送体の基質での治療を開始することを決定することであって、前記膜輸送体が、P-糖タンパク質(Pgp)、BCRP(乳癌耐性タンパク質)、およびOATP1B1から選択される、決定することと、
前記治療有効量の前記S1P 1 受容体調節剤の前記患者への投与を継続することと、を含む、方法。
〔10〕前記膜輸送体の前記基質に関連する毒性および臨床応答の徴候および症状について前記患者を監視することをさらに含む、前記〔9〕に記載の方法。
〔11〕前記膜輸送体の前記基質に関する1つ以上の曝露関連有害反応に耐容性である前記患者の能力に基づいて、前記患者に投与される前記膜輸送体の前記基質の量を低減することをさらに含む、前記〔9〕または〔10〕に記載の方法。
〔12〕前記患者または医療従事者に、前記S1P 1 受容体調節剤および膜輸送体の前記基質の同時投与が、前記膜輸送体の前記基質の曝露の増加をもたらし得ることを通知することをさらに含む、前記〔6〕~〔11〕のいずれか一項に記載の方法。
〔13〕前記患者または医療従事者に、前記S1P 1 受容体調節剤および前記膜輸送体の前記基質の同時投与が、前記膜輸送体の前記基質に関連する1つ以上の曝露関連有害反応のリスクの増加をもたらし得ることを通知することをさらに含む、前記〔6〕~〔12〕のいずれか一項に記載の方法。
〔14〕毒性および臨床応答の徴候および症状について監視することが、前記膜輸送体の前記基質の血清濃度を監視することを含む、前記〔6〕~〔13〕のいずれか一項に記載の方法。
〔15〕毒性および臨床応答の徴候および症状について監視することが、前記患者が、前記膜輸送体の前記基質の血清濃度に関連する1つ以上の曝露関連有害反応を経験するかを決定することを含む、前記〔6〕~〔13〕のいずれか一項に記載の方法。
〔16〕毒性および臨床応答の徴候および症状について監視することが、前記膜輸送体の前記基質の有効性を監視することを含む、前記〔6〕~〔13〕のいずれか一項に記載の方法。
〔17〕前記膜輸送体が、P-糖タンパク質である、前記〔6〕~〔13〕のいずれか一項に記載の方法。
〔18〕前記膜輸送体の前記基質が、ジゴキシン、ロペラミド、ベルベリン、イリノテカン、ドキソルビシン、ビンブラスチン、パクリタキセル、およびフェキソフェナジンから選択される、前記〔17〕に記載の方法。
〔19〕前記膜輸送体が、BCRPである、前記〔6〕~〔13〕のいずれか一項に記載の方法。
〔20〕前記膜輸送体の前記基質が、ミトキサントロン、メトトレキサート、トポテカン、イマチニブ、イリノテカン、スタチン、硫酸抱合体、およびポルフィリンから選択される、前記〔19〕に記載の方法。
〔21〕前記膜輸送体が、OATP1B1である、前記〔6〕~〔13〕のいずれか一項に記載の方法。
〔22〕前記膜輸送体の前記基質が、ブロモスルホフタレイン、エストロン-3-硫酸塩、エストラジオール-17β-グルクロニド、スタチン、レパグリニド、バルサルタン、オルメサルタン、ビリルビングルクロニド、ビリルビン、および胆汁酸から選択される、前記〔21〕に記載の方法。
〔23〕前記剤形が、絶食条件下で投与される、前記〔1〕~〔22〕のいずれか一項に記載の方法。
〔24〕前記剤形が、摂食条件下で投与される、前記〔1〕~〔22〕のいずれか一項に記載の方法。
〔25〕前記方法が、非性特異的である、前記〔1〕~〔24〕のいずれか一項に記載の方法。
〔26〕前記治療有効量が、約0.5~約5.0mgの化合物1に相当する、前記〔1〕~〔25〕のいずれか一項に記載の方法。
〔27〕前記個体に、TNFアンタゴニスト、インテグリンアンタゴニスト、および免疫抑制剤から選択される少なくとも1つの薬剤が以前に投与された、前記〔1〕~〔26〕のいずれか一項に記載の方法。
〔28〕前記個体に、ベドリズマブが以前に投与された、前記〔27〕に記載の方法。
〔29〕前記個体が、少なくとも1つの薬剤との不十分な応答を有したか、これに対する応答を喪失したか、またはこれに対して不耐性であった、前記〔1〕~〔28〕のいずれか一項に記載の方法。
〔30〕前記個体を活動性感染症について監視することをさらに含む、前記〔1〕~〔29〕のいずれか一項に記載の方法。
〔31〕前記個体が活動性感染症を発症した場合に投与を中止することをさらに含む、前記〔30〕に記載の方法。
〔32〕治療することが、臨床応答を誘導および/もしくは維持すること、粘膜の内視鏡的外観を改善すること、ならびに/または臨床寛解を誘導および/もしくは維持すること、を含む、前記〔1〕~〔31〕のいずれか一項に記載の方法。
〔33〕前記化合物1が、漸増なしで投与される、前記〔1〕~〔32〕のいずれか一項に記載の方法。
〔34〕前記投与することが、重篤な有害事象をもたらさない、前記〔1〕~〔33〕のいずれか一項に記載の方法。
〔35〕前記化合物1が、前記個体において急性心拍数低減または心臓ブロックを実質的に誘導することなく投与される、前記〔1〕~〔34〕のいずれか一項に記載の方法。
〔36〕前記S1P 1 受容体関連障害が、炎症性腸疾患である、前記〔1〕~〔35〕のいずれか一項に記載の方法。
〔37〕前記炎症性腸疾患が、潰瘍性大腸炎である、前記〔36〕に記載の方法。
〔38〕前記炎症性腸疾患が、中等度~重度活動性潰瘍性大腸炎である、前記〔37〕に記載の方法。
〔39〕前記炎症性腸疾患が、クローン病である、前記〔36〕に記載の方法。
〔40〕前記投与することの前に、前記個体が、少なくとも6の3コンポーネントメイヨークリニックスコアを有する、前記〔36〕に記載の方法。
〔41〕前記投与することが、前記個体の3コンポーネントメイヨークリニックスコアの改善をもたらす、前記〔36〕に記載の方法。
〔42〕前記投与することが、前記個体の2コンポーネントメイヨークリニックスコアの改善をもたらす、前記〔36〕に記載の方法。
〔43〕前記投与することが、前記個体のトータルメイヨークリニックスコアの改善をもたらす、前記〔36〕に記載の方法。
〔44〕前記投与することが、前記個体の前記粘膜の前記内視鏡的外観の改善をもたらす、前記〔36〕に記載の方法。
〔45〕前記投与することが、前記個体における臨床寛解を誘導することをもたらす、前記〔36〕に記載の方法。
〔46〕前記投与することが、前記個体における臨床寛解を維持することをもたらす、前記〔36〕に記載の方法。
〔47〕前記投与することが、前記個体における臨床寛解を誘導および維持することをもたらす、前記〔36〕に記載の方法。
〔48〕前記投与することが、前記個体における臨床応答を誘導することをもたらす、前記〔36〕に記載の方法。
〔49〕前記投与することが、前記個体における臨床応答を維持することをもたらす、前記〔36〕に記載の方法。
〔50〕前記投与することが、前記個体における臨床応答を誘導および維持することをもたらす、前記〔36〕に記載の方法。
〔51〕前記個体が、前記化合物1が投与される前に絶食している、前記〔1〕~〔50〕のいずれか一項に記載の方法。
〔52〕前記治療有効量が、1mgの化合物1に相当する量である、前記〔1〕~〔51〕のいずれか一項に記載の方法。
〔53〕前記治療有効量が、2mgの化合物1に相当する量である、前記〔1〕~〔51〕のいずれか一項に記載の方法。
〔54〕前記治療有効量が、3mgの化合物1に相当する量である、前記〔1〕~〔51〕のいずれか一項に記載の方法。
〔55〕前記治療有効量の化合物1、またはその薬学的に許容される塩、水和物、もしくは溶媒和物が、1日1回前記個体に投与される、前記〔1〕~〔54〕のいずれか一項に記載の方法。
〔56〕化合物1、またはその薬学的に許容される塩、水和物、もしくは溶媒和物の投与中に有害事象について監視することと、任意選択的に、化合物1、またはその薬学的に許容される塩、水和物、もしくは溶媒和物の投与を中断または終了することと、をさらに含む、前記〔1〕~〔55〕のいずれか一項に記載の方法。
〔57〕前記化合物1、またはその薬学的に許容される塩、水和物、もしくは溶媒和物が、経口投与される、前記〔1〕~〔56〕のいずれか一項に記載の方法。
〔58〕前記化合物1、またはその薬学的に許容される塩、水和物、もしくは溶媒和物が、経口投与に好適なカプセルまたは錠剤として製剤化される、前記〔1〕~〔57〕のいずれか一項に記載の方法。
〔59〕前記化合物1、またはその薬学的に許容される塩、水和物、もしくは溶媒和物が、
化合物1、
化合物1のカルシウム塩、および
化合物1のL-アルギニン塩から選択される、前記〔1〕~〔58〕のいずれか一項に記載の方法。
〔60〕前記化合物1、またはその薬学的に許容される塩、水和物、もしくは溶媒和物が、化合物1のL-アルギニン塩である、前記〔1〕~〔59〕のいずれか一項に記載の方法。
〔61〕前記化合物1、またはその薬学的に許容される塩、水和物、もしくは溶媒和物が、化合物1のL-アルギニン塩の無水非溶媒和結晶形態である、前記〔1〕~〔58〕のいずれか一項に記載の方法。
〔62〕前記化合物1、またはその薬学的に許容される塩、水和物、もしくは溶媒和物が、化合物1の無水非溶媒和結晶形態である、前記〔1〕~〔58〕のいずれか一項に記載の方法。
〔63〕前記CYP基質が、CYP2C8基質である、前記〔1〕~〔62〕のいずれか一項に記載の方法。
〔64〕前記CYP基質が、CYP2C9基質である、前記〔1〕~〔63〕のいずれか一項に記載の方法。
〔65〕前記UGT基質が、UGT1A1基質である、前記〔1〕~〔64〕のいずれか一項に記載の方法。
〔66〕前記UGT基質が、UGT1A4基質である、前記〔1〕~〔65〕のいずれか一項に記載の方法。
〔67〕前記UGT基質が、UGT1A6基質である、前記〔1〕~〔66〕のいずれか一項に記載の方法。
〔68〕前記UGT基質が、UGT1A7基質である、前記〔1〕~〔67〕のいずれか一項に記載の方法。
〔69〕前記OAT基質が、OATP1B1基質である、前記〔1〕~〔68〕のいずれか一項に記載の方法。
〔70〕前記OAT基質が、OATP1B3基質である、前記〔1〕~〔69〕のいずれか一項に記載の方法。
〔71〕前記OAT基質が、OAT1基質である、前記〔1〕~〔70〕のいずれか一項に記載の方法。
〔72〕前記OAT基質が、OAT3基質である、前記〔1〕~〔71〕のいずれか一項に記載の方法。
〔73〕前記CYP2C8阻害剤、CYP2C9阻害剤、CYP2C8誘導剤、またはCYP2C9誘導剤が、フルコナゾールである、前記〔1〕~〔72〕のいずれか一項に記載の方法。
〔74〕前記CYP2C8阻害剤、CYP2C9阻害剤、CYP2C8誘導剤、またはCYP2C9誘導剤が、ゲムフィブロジルである、前記〔1〕~〔73〕のいずれか一項に記載の方法。
〔75〕前記CYP2C8阻害剤、CYP2C9阻害剤、CYP2C8誘導剤、またはCYP2C9誘導剤が、リファンピンである、前記〔1〕~〔74〕のいずれか一項に記載の方法。
〔76〕OATP1B1の前記基質が、リファンピンである、前記〔1〕~〔75〕のいずれか一項に記載の方法。
〔77〕OATP1B3の前記基質が、リファンピンである、前記〔1〕~〔76〕のいずれか一項に記載の方法。
〔78〕CYP基質、OAT基質、UGT基質、CYP2C8阻害剤、CYP2C9阻害剤、CYP2C8誘導剤、CYP2C9誘導剤、UGT1A1阻害剤、またはUGT1A6阻害剤を投与されていない患者に投与される量未満が、CYP基質、OAT基質、UGT基質、CYP2C8阻害剤、CYP2C9阻害剤、CYP2C8誘導剤、CYP2C9誘導剤、UGT1A1阻害剤、またはUGT1A6阻害剤を投与されていない患者に投与される量より約、少なくとも、または少なくとも約1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、778、79、80、81、82、83、84、85、86、87、88、89、または90%少ない、前記〔1〕~〔77〕のいずれか一項に記載の方法。
〔79〕CYP基質、OAT基質、UGT基質、CYP2C8阻害剤、CYP2C9阻害剤、CYP2C8誘導剤、CYP2C9誘導剤、UGT1A1阻害剤、またはUGT1A6阻害剤を投与されていない患者に投与される量未満が、CYP基質、OAT基質、UGT基質、CYP2C8阻害剤、CYP2C9阻害剤、CYP2C8誘導剤、CYP2C9誘導剤、UGT1A1阻害剤、またはUGT1A6阻害剤を投与されていない患者に投与される量より約、少なくとも、または少なくとも約0.1、0.2、0.25、0.3、0.4、0.5、0.6、0.7、0.75、0.8、0.9、1.0、1.1、1.2、1.25、1.3、1.4、1.5、1.6、1.7、1.75、1.8、1.9、または2.0mg少ない、前記〔1〕~〔78〕のいずれか一項に記載の方法。
〔80〕(R)-2-(7-(4-シクロペンチル-3-(トリフルオロメチル)ベンジルオキシ)-1,2,3,4-テトラヒドロシクロペンタ[b]インドール-3-イル)酢酸(化合物1)、またはその薬学的に許容される塩、水和物、もしくは溶媒和物から選択されるスフィンゴシン1-リン酸サブタイプ1(S1P 1 )受容体調節剤を、それを必要とする患者に安全に投与する方法であって、前記患者が、CYP基質、OAT基質、またはUGT基質も投与されており、前記患者に2mg未満の1日用量の前記S1P 1 調節剤を投与することを含む、方法。
〔81〕前記S1P 1 調節剤の1日用量が、1.0、1.25、1.5、および1.75mgの前記S1P 1 調節剤から選択される、前記〔76〕に記載の方法。
Claims (12)
- (R)-2-(7-(4-シクロペンチル-3-(トリフルオロメチル)ベンジルオキシ)-1,2,3,4-テトラヒドロシクロペンタ[b]インドール-3-イル)酢酸(化合物1)、またはその薬学的に許容される塩、水和物、もしくは溶媒和物を含む、スフィンゴシン1-リン酸サブタイプ1(S1P1)受容体関連障害を有する個体を治療する方法に使用するための薬学的投与剤であって、
前記スフィンゴシン1-リン酸サブタイプ1(S1P1)受容体関連障害が、自己免疫性疾患または障害、炎症性疾患または障害、強直性脊椎炎、胆汁性肝硬変、癌、乾癬、乾癬性関節炎、リウマチ姓関節炎、クローン病、移植拒絶、多発性硬化症、全身性紅斑性狼瘡、炎症性腸疾患、潰瘍性大腸炎、I型糖尿病、高血圧性腎症、糸球体硬化症、心筋虚血-再灌流傷害、ならびにざ瘡から選択され、
前記方法が、治療を必要とする前記個体に、前記薬学的投与剤を摂食条件で投与することを含み、および
前記薬学的投与剤が0.5~5.0mgの化合物1を含む、
上記薬学的投与剤。 - 前記薬学的投与剤が2.0mgの化合物1を含む、請求項1記載の薬学的投与剤。
- 前記方法が、非性特異的である、請求項1または2に記載の薬学的投与剤。
- 前記方法が、前記個体を活動性感染症について監視することをさらに含む、請求項1~3のいずれか一項に記載の薬学的投与剤。
- 前記方法が、前記個体が活動性感染症を発症した場合に投与を中止することをさらに含む、請求項4に記載の薬学的投与剤。
- 治療することが、臨床応答を誘導および/もしくは維持すること、粘膜の内視鏡的外観を改善すること、ならびに/または臨床寛解を誘導および/もしくは維持すること、を含む、請求項1~5のいずれか一項に記載の薬学的投与剤。
- 前記化合物1が、漸増なしで投与される、請求項1~6のいずれか一項に記載の薬学的投与剤。
- 前記方法が、重篤な有害事象をもたらさない、請求項1~7のいずれか一項に記載の薬学的投与剤。
- 前記化合物1が、前記個体において急性心拍数低減または心臓ブロックを実質的に誘導することなく投与される、請求項1~8のいずれか一項に記載の薬学的投与剤。
- 前記S1P1受容体関連障害が、炎症性腸疾患である、請求項1~9のいずれか一項に記載の薬学的投与剤。
- 前記炎症性腸疾患が、潰瘍性大腸炎である、請求項10に記載の薬学的投与剤。
- 前記炎症性腸疾患が、中等度~重度活動性潰瘍性大腸炎である、請求項11に記載の薬学的投与剤。
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KR20210029190A (ko) | 2021-03-15 |
CA3102136A1 (en) | 2019-12-12 |
IL279180A (en) | 2021-01-31 |
CN112601516A (zh) | 2021-04-02 |
AU2019280822A1 (en) | 2021-01-07 |
WO2019236757A1 (en) | 2019-12-12 |
AU2019280822A8 (en) | 2021-01-28 |
MA52778A (fr) | 2021-04-21 |
BR112020024762A2 (pt) | 2021-03-23 |
EP3801459A1 (en) | 2021-04-14 |
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