JP7032322B2 - ビタミンd治療法 - Google Patents
ビタミンd治療法 Download PDFInfo
- Publication number
- JP7032322B2 JP7032322B2 JP2018550792A JP2018550792A JP7032322B2 JP 7032322 B2 JP7032322 B2 JP 7032322B2 JP 2018550792 A JP2018550792 A JP 2018550792A JP 2018550792 A JP2018550792 A JP 2018550792A JP 7032322 B2 JP7032322 B2 JP 7032322B2
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- Prior art keywords
- hydroxyvitamin
- serum
- dihydroxyvitamin
- patient
- vitamin
- Prior art date
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Description
2016年3月28日に出願された米国仮特許出願第62/314,359号の利益が、米国特許法第119条の下で本明細書で主張され、その開示が、参照により本明細書に組み込まれる。
CKDステージ3または4の患者における延長放出25-ヒドロキシビタミンD3の第III相臨床試験
25-ヒドロキシビタミンD3の延長放出製剤(RAYALDEE、Opko Ireland Global Holdings Ltd.)の有効性と安全性を、二次性副甲状腺機能亢進症(iPTH>85pg/mL)、ステージ3または4の慢性腎疾患及び関連した血清総25-ヒドロキシビタミンDレベル≧10ng/mLかつのと≦30ng/mLを有する患者を対象にした2つの同一の多施設、無作為化、プラセボ対照、二重盲検試験において評価した。対象を病期別に層別化し、2:1の比率で無作為化して、RAYALDEE(またはマッチするプラセボ)の経口用量30mcgを1日1回、就寝時に12週間服用させ、続いてさらに14週間、RAYALDEE(またはプラセボ)の30または60mcgのいずれかの1日1回の経口用量で就寝時に処置する。各カプセルには、以下の賦形剤:鉱油、モノグリセリドならびにジグリセリド、パラフィン、ヒプロメロース、ラウロイルポリオキシルグリセリド、脱水アルコール及びブチルヒドロキシトルエンが含まれていた。カプセルシェルには、変性デンプン、カラギーナン、リン酸ナトリウム、二塩基性ソルビトールソルビタン溶液、FD&C Blue#1、二酸化チタン及び精製水が含まれていた。中鎖トリグリセリド(分留ココナッツ)油を製造中に滑沢剤として使用したので、微量が最終配合物中に存在していた可能性がある。
薬物動態試験
RAYALDEEの薬物動態を、健康な対象及びCKDステージ3またはステージ4の対象において評価した。二次性副甲状腺機能亢進症、慢性腎疾患及びビタミンD不足の対象に対して、就寝時にRAYALDEEを毎日反復投与した後、カルシフェジオールへの暴露を30~90mcgの用量範囲にわたって比例して増加させた。血清総25-ヒドロキシビタミンDの定常状態レベルには、約3ヶ月後に達した。RAYALDEEを複数回投与した後の血清総25-ヒドロキシビタミンDの平均定常状態濃度は、30mcg及び60mcgの用量群について、それぞれ53ng/mL及び68ng/mLであった。分布に関しては、カルシフェジオールは血漿タンパク質に広く結合している(>98%)。分布の平均の見かけの体積は、RAYALDEEの単回経口投与後の健康な対象で8.8Lであって、繰り返し投与後のステージ3またはステージ4の慢性腎疾患を有する対象において30.1Lであった。排泄に関して、カルシフェジオールの平均排泄半減期は、RAYALDEEの単回投与後の健常者では約11日間であり、1日1回の投与を繰り返した後のステージ3またはステージ4の慢性腎疾患患者では約25日間であった。代謝に関して、カルシフェジオールからのカルシトリオールの産生は、腎臓、副甲状腺、及び他の組織に位置する1α-ヒドロキシラーゼ酵素CYP27B1によって触媒される。全てのビタミンD応答性組織に位置するCYP24A1は、カルシフェジオール及びカルシトリオールの両方を不活性代謝物に異化する。カルシトリオールはCYP27B1を抑制し、CYP24A1をアップレギュレートする。カルシフェジオールの排泄は、主に胆道の糞便経路を通して起こる。CKDステージ3またはステージ4の対象における集団の薬物動態の分析において、定常状態のカルシフェジオール濃度に対するCKDステージの影響は、RAYALDEEの毎日の投与後に明らかではなかった。表1は、処置群によるカルシフェジオールのベースライン調整された薬物動態パラメーターの要約を示す。
CKDステージ5の患者における延長放出25-ヒドロキシビタミンD3の臨床試験
副次的副甲状腺機能亢進症、ビタミンD不足及び血液透析を1週間に3回受けているCKDステージ5の対象において、血清中の副甲状腺ホルモン(iPTH)の前処置ベースラインからの少なくとも30%の減少における、プラセボに対する25-ヒドロキシビタミンD3の延長放出製剤の3週間の用量の安全性及び有効性を評価するために、多施設無作為化二重盲検プラセボ対照臨床試験を実施する。25-ヒドロキシビタミンD3の延長放出製剤は、RAYALDEEと同じ処方を有するが、150mcgの25-ヒドロキシビタミンD3を含有するカプセルとして提供される。およそ600人の対象をスクリーニングして、SHPTの重症度をバランスさせた約280人の適格対象を1:1:1:1の割合で、以下の処置を52週間受ける4つの並列群にランダム化する:(a)週当たり300mcgでの25-ヒドロキシビタミンD3の延長放出製剤、(b)週当たり600mcgでの25-ヒドロキシビタミンD3の延長放出製剤、(c)週当たり900mcgでの25-ヒドロキシビタミンD3の延長放出製剤、または(d)の釣り合う用量のプラセボ。
血清1,25-ジヒドロキシビタミンDの超生理的レベルまでの安全な上昇
図8及び図9は、2名の対象において、最長1年まで延長放出経口カルシフェジオールを投与した対象を伴う試験からの初期の結果を示す。
Claims (11)
- 患者の治療方法に使用するための、25-ヒドロキシビタミンDを含む組成物であって、前記方法は、慢性腎疾患ステージ3またはステージ4、20を超える血清25-ヒドロキシビタミンDの血清24,25-ジヒドロキシビタミンDに対する患者の血清比、及び少なくとも30ng/mLの血清25-ヒドロキシビタミンDレベルを有する患者を選択すること、ならびに、反復用量の25-ヒドロキシビタミンDを投与して、前記患者の血清25-ヒドロキシビタミンDレベルを90ng/mlを超えて安全に上昇させる、及び、前記患者の25-ヒドロキシビタミンDの24,25-ジヒドロキシビタミンDに対する血清比を20未満に制御することを含む、組成物。
- 前記反復用量が、少なくとも3ヶ月間投与される、請求項1に記載の組成物。
- 前記方法が、前記患者の血清25-ヒドロキシビタミンDレベルを100ng/mlを超えて安全に上昇させる、請求項1~2のいずれか一項に記載の組成物。
- 前記方法が、前記患者の25-ヒドロキシビタミンDの24,25-ジヒドロキシビタミンDに対する血清比を15未満に制御する、請求項1~3のいずれか一項に記載の組成物。
- 前記反復用量の25-ヒドロキシビタミンDが、制御放出経口製剤として投与される、請求項1~4のいずれか一項に記載の組成物。
- 前記制御放出経口製剤が、カルシフェジオールの経口延長放出製剤を含む、請求項5に記載の組成物。
- 前記製剤が、約30mcgの25-ヒドロキシビタミンD3、ワックス状制御放出剤、乳化剤、吸収促進剤、油性ビヒクル、及び安定化剤を含む、請求項6に記載の組成物。
- 前記製剤が、約60mcgの25-ヒドロキシビタミンD3、ワックス状制御放出剤、乳化剤、吸収促進剤、油性ビヒクル、及び安定化剤を含む、請求項6に記載の組成物。
- 前記製剤が、CKDステージ3またはステージ4を有する患者に投与されるとき、反復投薬後に1,25-ジヒドロキシビタミンDについての以下のベースライン調整された薬物動態パラメーター:(1)約1pg/mL~約21pg/mLのCmax、及び(2)約1g・d/mL~約460g・d/mLのAUC0~6週のうちの1つ以上を有し、任意に、約1日~約44日のTmaxをさらに有する、或いは、反復投薬後に25-ヒドロキシビタミンD3についての以下のベースライン調整された薬物動態パラメーター:(1)約10ng/mL~約45ng/mLのCmax、及び(2)約300ng・d/mL~約1300ng・d/mLのAUC0~6週のうちの1つ以上を有し、任意に、約8日~約45日のTmaxをさらに有する、請求項8に記載の組成物。
- 前記製剤が、CKDステージ3またはステージ4を有する患者に投与されるとき、反復投薬後に1,25-ジヒドロキシビタミンDについての以下のベースライン調整された薬物動態パラメーター:(1)約7pg/mL~約30pg/mLのCmax、及び(2)約1g・d/mL~約570g・d/mLのAUC0~6週のうちの1つ以上を有し、任意に、約8日~約44日のTmaxをさらに有する、或いは、反復投薬後に25-ヒドロキシビタミンD3についての以下のベースライン調整された薬物動態パラメーター:(1)約30ng/mL~約90ng/mLのCmax、及び(2)約700ng・d/mL~約2300ng・d/mLのAUC0~6週のうちの1つ以上を有し、任意に、約29日~約45日のTmaxをさらに有する、請求項8に記載の組成物。
- 25-ヒドロキシビタミンDの反復投薬が、ベースラインと比較して、前記患者の血漿PTHレベルを少なくとも15%、任意には少なくとも30%低下させるのに有効である、請求項1~10のいずれか一項に記載の組成物。
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