JP2021529732A - 大うつ病性障害の処置方法 - Google Patents
大うつ病性障害の処置方法 Download PDFInfo
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Abstract
Description
この出願は、2018年6月27日に出願された米国仮出願第62/690,419号、2018年7月16日に出願された62/698,323号、2018年10月5日に出願された62/741,564号、および2018年11月19日に出願された62/769,264の利益を主張し、それぞれの全体が引用により本明細書に包含される。
●任意の水素原子または水素原子の基は、水素の同位体、すなわち重水素に適切に置換することができ、
●任意の炭素原子または炭素原子の基は、炭素の同位体、すなわち13Cの同位体に置換することができ、かつ
●任意の窒素原子または窒素原子の基は、窒素の同位体、すなわち、15Nに適切に置換することができる。
実施例1a:エスケタミン
エスケタミンの染色体異常誘発能を、誘発代謝活性化系(Aroclor−1254に曝露されたラットからの肝臓ホモジネートの9000g上清[S9]ミクロソーム画分)の非存在下および存在下の両方で、ヒト末梢血リンパ球(HPBL)を使用するインビトロ哺乳類染色体異常試験で評価した。染色体異常誘発性を、中期のHPBLの顕微鏡検査によって評価し、有糸分裂指数(MI)および数値的および/または構造的染色体異常を伴う中期細胞の割合を決定した。
S−ノルケタミンの染色体異常誘発能を、誘発代謝活性化系(フェノバルビタール/5,6−ベンゾフラボンに暴露されたラットからの肝臓ホモジネートの9000g上清[S9]ミクロソーム画分)の非存在下と存在下の両方で、ヒト末梢血リンパ球(HPBL)を使用したインビトロ哺乳類染色体異常試験で評価した。染色体異常誘発性を、中期におけるHPBLの顕微鏡検査によって評価し、数値的および/または構造的染色体異常を伴う中期細胞の割合を決定した。
エスケタミンが、肝臓でDNA鎖切断を誘発する可能性、およびCrl:CD(SD)ラットの骨髄細胞で微小核を誘発する可能性を評価する。動物にエスケタミンを3回経口投与し、2回目の投与は1回目の投与の約24時間後に投与し、3回目の投与は2回目の投与の約21時間後、サンプリングの3時間前に投与した。すべての動物に、10mL/kgの投与容量を使用する強制給餌により経口投与した。
この試験の目的は、エスケタミンをSprague Dawleyラットに強制給餌により28日にわたり経口投与した場合の潜在的毒性、神経行動学的影響、および毒物動態(TK)を評価し、14日間の無薬期間中の回復を評価することであった。50匹のオスおよび50匹のメスラットをランダムに4つの群に分けた(15匹/雌雄/群1および4、10匹/雌雄/群2および3)。エスケタミンを、0(ビヒクル対照)、6、10または30mg/kg/日でオスに、および0(ビヒクル対照)、2、10または20mg/kg/日でメスに、28日間連続して1日1回、10mL/kgの用量容量で強制給餌により経口投与した。29日目(10匹/雌雄/群)または43日目(5匹/群1および4からの雌雄)を安楽死させて剖検するまで、動物を観察した。毒性を、死亡率、臨床観察、体重、食物消費、眼科、運動活性、機能的観察バッテリー、臨床病理学(臨床化学、血液学、凝固および尿検査)、臓器重量、解剖学的(肉眼的または顕微鏡的)病理学に基づいて評価した。毒物動態学分析のために、毒物動態動物(3匹/雌雄/群1、6匹/雌雄/群2、3、および4)に同様に投与し、1日目と4週目に採血した。
Sprague Dawley Ratに、強制給餌により経口投与したエスケタミンの104週間の発がん性試験を実施し、発がん性の可能性を評価し、エスケタミンの毒物動態を測定する。
6〜7週齢のオスのSprague Dawleyラットの群に、エスケタミンを腹腔内注射によって投与し、行動の断念を強制水泳試験によって評価した。10コホートの動物に、15mg/kgのエスケタミンの単回用量、7.5または15mg/kgのエスケタミンまたはビヒクル対照の7回の1日用量のいずれかを投与し、投与の30分後に試験を実施した。統計学的評価を、通常の一元配置分散分析、t検定、および未修正のフィッシャーのLSD比較検定を使用して実施した。
16人の健康な男性および女性の被験者において、ランダム化、非盲検4方向クロスオーバー試験を実施し、ここで当該被験者をランダムに割り当てられた順序で配置し、エスケタミンを投与した。各被験者を、4人の被験者が各処置配列に割り当てられるように、ランダム化コードに従って4つの処置配列のうちの1つに割り当てた。経口または静脈内エスケタミン塩酸塩からなる投与による投与期間の間に、少なくとも7日間のウォッシュアウト期間があった。この試験は、28日間の適格性スクリーニング期間、エスケタミン塩酸塩の単回用量を含む4つの試験期間、続いて治験薬投与後72時間までのPK目的の採血による安全性評価、治験薬投与後72時間での退院、4日目に最後のPK血液サンプルを採取してから7〜14日後のフォローアップ訪問からなった。
フェーズII、用量範囲の所見、多国籍、二重ランダム化、二重盲検、プラセボ対照試験は、抗うつ治療に不十分な応答を有する204人のMDD被験者を対象において、1日1回の10、20、または40mg経口エスケタミンの有効性、安全性、および耐容性を、プラセボ処置と比較する。すべての被験者は、現在の彼らの抗うつ薬を、試験中に用量を変更することなく使用したままとする。
Claims (23)
- 大うつ病性障害(MDD)の処置を必要とするヒト患者においてMDDを処置する方法であって、少なくとも28日間の処置レジメンにわたるエスケタミンの前記患者への投与を含み、
a.前記投与のエスケタミンCmaxが30ng/ml以下であり、または
b.前記投与のエスケタミンAUC0−tが60ng*h/ml以下であり、または
c.前記投与の前記エスケタミンCmaxが、30ng/ml以下であり、かつ前記投与の前記AUC0−tが60ng*h/ml以下である、方法。 - 前記処置レジメンが、28日から約730日である、請求項1に記載の方法。
- 前記処置レジメンが、28日から約365日である、請求項1に記載の方法。
- 前記投与が毎日である、請求項1から3のいずれか一項に記載の方法。
- 前記投与が、2日ごとに1回から月に1回の期間にわたって断続的である、請求項1から3のいずれか一項に記載の方法。
- 前記投与が週に2回である、請求項5に記載の投与。
- 前記投与が週に1回である、請求項5に記載の投与。
- 前記投与が月に1回である、請求項5に記載の投与。
- 前記断続的な投与の頻度が、前記処置レジメンにわたって変化する、請求項5に記載の投与。
- 前記投与が経口的である、請求項1から9のいずれか一項に記載の方法。
- 前記投与が非経口的である、請求項1から9のいずれか一項に記載の方法。
- 前記投与が静脈内である、請求項11に記載の方法。
- 前記投与が鼻腔内である、請求項11に記載の方法。
- 前記投与が直腸である、請求項11に記載の方法。
- 前記投与が舌下である、請求項11に記載の方法。
- 前記投与が頬側である、請求項11に記載の方法。
- (R)−ケタミン以外の第2の薬剤の投与をさらに含む、請求項1から16のいずれか一項に記載の方法。
- 前記第2の薬物が、抗うつ薬、抗躁薬、または抗不安薬である、請求項17に記載の方法。
- 前記抗うつ薬が、フルオキセチン、セルトラリン、パロキセチン、シタロプラム、エスシタロプラムおよびフルボキサミンからなる群から選択される、請求項18に記載の方法。
- 前記投与の前記エスケタミンCmaxが、15ng/ml以下である、請求項1から19のいずれか一項に記載の方法。
- 前記投与の前記エスケタミンAUC0−tが、30ng*h/ml以下である、請求項1から20のいずれか一項に記載の方法。
- 前記投与の前記エスケタミンCmaxが、30ng/ml以下であり、かつ前記投与の前記エスケタミンAUC0−tが60ng*h/ml以下である、請求項1から21のいずれか一項に記載の方法。
- 前記投与の前記エスケタミンCmaxが、15ng/ml以下であり、かつ前記投与の前記エスケタミンAUC0−tが30ng*h/ml以下である、請求項1から22のいずれか一項に記載の方法。
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