JP6882205B2 - 重度腎機能障害を有する癌患者に対する治療方法 - Google Patents
重度腎機能障害を有する癌患者に対する治療方法 Download PDFInfo
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Description
現在、FTDとTPIをモル比1:0.5で含有する配合剤(以下、「FTD・TPI配合剤」とも称す)は、固形癌の治療剤として開発中であり、米国においては進行・再発の結腸直腸癌の治療剤として、商品名ロンサーフ配合錠として承認されている(非特許文献1及び2)。臨床におけるFTD・TPI配合剤の用法用量は、通常、成人には、体表面積を基準に、FTDとして70mg/m2/日を、1日2回、5日間連続経口投与したのち2日間休薬する。これを2回繰り返したのち14日間休薬する。これを1サイクルとして投与を繰り返す、と定義されている。
一般に、腎機能障害患者への薬物投与は、腎機能の程度に応じた投与量又は投与間隔の調節が必要とされ、上記FDAガイダンスによれば薬物動態(PK)に基づいて用量を選択することが推奨されている。
しかしながら、重度の腎機能障害を有する癌患者に対してより安全で、かつ有効性の高い癌治療を行うことは容易ではない。
〔1〕クレアチニンクリアランスが30mL/min未満である患者における癌の治療方法であって、α,α,α−トリフルオロチミジン(FTD)と5−クロロ−6−[(2−イミノピロリジン−1−イル)メチル]ピリミジン−2,4(1H,3H)−ジオン塩酸塩をモル比1:0.5で含有する配合剤を、FTD換算量として30〜50mg/m2/日の用量を1日2〜4回に分割して前記患者に経口投与することを含む、治療方法。
〔2〕患者が、クレアチニンクリアランスが15mL/min以上29mL/min以下の患者である、〔1〕記載の癌の治療方法。
〔3〕FTD換算量として40mg/m2/日の用量を1日2回に分割して経口投与する、〔1〕又は〔2〕記載の癌の治療方法。
〔4〕投与スケジュールが、1週あたり、5日間連続経口投与2日間休薬である、〔1〕〜〔3〕のいずれか1に記載の癌の治療方法。
〔5〕投与スケジュールが、5日間連続経口投与2日間休薬を2回繰り返したのち14日間休薬である、〔1〕〜〔4〕のいずれか1に記載の癌の治療方法。
〔6〕癌が、消化器癌又は乳癌である、〔1〕〜〔5〕のいずれか1に記載の癌の治療方法。
〔7〕癌が、大腸癌である、〔1〕〜〔6〕のいずれか1に記載の癌の治療方法。
〔8〕クレアチニンクリアランスが30mL/min未満である患者における癌の治療剤であって、α,α,α−トリフルオロチミジン(FTD)と5−クロロ−6−[(2−イミノピロリジン−1−イル)メチル]ピリミジン−2,4(1H,3H)−ジオン塩酸塩をモル比1:0.5で含有する配合剤が、FTD換算量として30〜50mg/m2/日の用量を1日2〜4回に分割して前記患者に経口投与される、治療剤。
〔9〕患者が、クレアチニンクリアランスが15mL/min以上29mL/min以下の患者である、〔8〕記載の癌の治療剤。
〔10〕FTD換算量として40mg/m2/日の用量を1日2回に分割して経口投与される、〔8〕又は〔9〕記載の癌の治療剤。
〔11〕投与スケジュールが、1週あたり、5日間連続経口投与2日間休薬である、〔8〕〜〔10〕のいずれか1に記載の癌の治療剤。
〔12〕投与スケジュールが、5日間連続経口投与2日間休薬を2回繰り返したのち14日間休薬である、〔8〕〜〔11〕のいずれか1に記載の癌の治療剤。
〔13〕癌が、消化器癌又は乳癌である、〔8〕〜〔12〕のいずれか1に記載の癌の治療剤。
〔14〕癌が、大腸癌である、〔8〕〜〔13〕のいずれか1に記載の癌の治療剤。
〔15〕クレアチニンクリアランスが30mL/min未満である患者における癌の治療剤を製造するためのα,α,α−トリフルオロチミジン(FTD)と5−クロロ−6−[(2−イミノピロリジン−1−イル)メチル]ピリミジン−2,4(1H,3H)−ジオン塩酸塩をモル比1:0.5で含有する配合剤の使用であって、前記配合剤が、FTD換算量として30〜50mg/m2/日の用量を1日2〜4回に分割して前記患者に経口投与される、使用。
〔16〕患者が、クレアチニンクリアランスが15mL/min以上29mL/min以下の患者である、〔15〕記載の使用。
〔17〕FTD換算量として40mg/m2/日の用量を1日2回に分割して経口投与される、〔15〕又は〔16〕記載の使用。
〔18〕投与スケジュールが、1週あたり、5日間連続経口投与2日間休薬である、〔15〕〜〔17〕のいずれか1に記載の使用。
〔19〕投与スケジュールが、5日間連続経口投与2日間休薬を2回繰り返したのち14日間休薬である、〔15〕〜〔18〕のいずれか1に記載の使用。
〔20〕癌が、消化器癌又は乳癌である、〔15〕〜〔19〕のいずれか1に記載の使用。
〔21〕癌が、大腸癌である、〔15〕〜〔20〕のいずれか1に記載の使用。
〔22〕クレアチニンクリアランスが30mL/min未満である患者における癌の治療に使用するためのα,α,α−トリフルオロチミジン(FTD)と5−クロロ−6−[(2−イミノピロリジン−1−イル)メチル]ピリミジン−2,4(1H,3H)−ジオン塩酸塩をモル比1:0.5で含有する配合剤であって、FTD換算量として30〜50mg/m2/日の用量を1日2〜4回に分割して前記患者に経口投与される、配合剤。
〔23〕患者が、クレアチニンクリアランスが15mL/min以上29mL/min以下の患者である、〔22〕記載の配合剤。
〔24〕FTD換算量として40mg/m2/日の用量を1日2回に分割して経口投与される、〔22〕又は〔23〕記載の配合剤。
〔25〕投与スケジュールが、1週あたり、5日間連続経口投与2日間休薬である、〔22〕〜〔24〕のいずれか1に記載の配合剤。
〔26〕投与スケジュールが、5日間連続経口投与2日間休薬を2回繰り返したのち14日間休薬である、〔22〕〜〔25〕のいずれか1に記載の配合剤。
〔27〕癌が、消化器癌又は乳癌である、〔22〕〜〔26〕のいずれか1に記載の配合剤。
〔28〕癌が、大腸癌である、〔22〕〜〔27〕のいずれか1に記載の配合剤。
FTD及びTPIはそれぞれ公知の化合物であり、例えば、国際公開第1996/30346号パンフレットに記載の方法に従って合成することができる。また、FTD・TPI配合剤も公知である(非特許文献1及び2)。また、錠剤形態のFTD・TPI配合剤は、米国において進行・再発の結腸直腸癌の治療剤として承認されている。
FTD・TPI配合剤の用量は、FTD換算量として30〜50mg/m2/日であるが、好ましくは30〜48mg/m2/日であり、好ましくは35〜45mg/m2/日であり、好ましくは40mg/m2/日である。
1.The Mosteller formula(N Engl J Med 1987 Oct 22;317(17):1098(letter)参照)
BSA(m2)=([身長(cm)×体重(kg)]/3600)1/2
2.The DuBois and DuBois formula(Arch Int Med 1916 17:863−71;J Clin Anesth.1992;4(1):4−10参照)
(a)BSA(m2)=0.20247×身長(m)0.725×体重(kg)0.425
(b)BSA(m2)=0.007184×身長(cm)0.725×体重(kg)0.425
3.The Haycock formula(The Journal of Pediatrics 1978 93:1:62−66参照)
BSA(m2)=0.024265×身長(cm)0.3964×体重(kg)0.5378
4.The Gehan and George formula(Cancer Chemother Rep 1970 54:225−35参照)
BSA(m2)=0.0235×身長(cm)0.42246×体重(kg)0.51456
5.The Boyd formula(Minneapolis:university of Minnesota Press,1935参照)
BSA(m2)=0.0003207×身長(cm)0.3×体重(grams)(0.7285-(0.0188 x LOG(grams))
6.The Fujimoto formula(Nihon Eiseigaku Zasshi、1968 23(5):443−450参照)
BSA(m2)=0.008883×身長(cm)0.663×体重(kg)0.444
患者のCLcrの値は腎機能の指標であり、CLcrが15〜29mL/minの患者は、重度の腎機能障害を有する患者(重度腎機能障害患者)を含む。重度腎機能障害患者は高度腎機能障害患者ともいう。
[Cockcroft−Gault式]
男性:CLcr(mL/min)={(140−年齢)×体重(kg)}÷{血清クレアチニン値(mg/dL)×72}
女性:CLcr(mL/min)={(140−年齢)×体重(kg)}÷{血清クレアチニン値(mg/dL)×72}×0.85
なお、血清クレアチニン値は、常法により測定することができる。
結腸/・直腸癌を含む固形癌の患者を対象に、FTD・TPI配合剤(FTDとTPIとのモル比1:0.5の混合物)1回35mg/m2(FTDとして、以下、同様)を1日2回5日間連続経口投与し2日間休薬する投与スケジュールを2回繰り返した後、14日間休薬することを1サイクルとして繰り返す治療を行った際のFTDの薬物動態を検討した。
患者は、投与開始前に上記Cockcroft−Gault式によりCLcrの値を算出して腎機能を評価し、コントロール(正常、CLcr:≧90mL/min)、軽度(CLcr:60〜89mL/min)、中等度(CLcr:30〜59mL/min)に群分けした。FTD・TPI配合剤投与後1日目および12日目の投与前および投与後0.5、1、2、4、6、8、10、12時間に採血を実施し、血漿中FTDおよびTPI濃度を測定した。得られた血漿中濃度を用いてFTDおよびTPIの薬物動態パラメータを算出し、結果を表1に示した。
重度腎機能障害患者に適切な投与量を決定するため、投与後12日目のFTDの経口クリアランス(CL/F)とクレアチニンクリアランス(CLcr)の回帰分析を行った。結果を図1に示す。
FTD CL/F (L/hr) = 0.3432 × CLcr (mL/min)0.4870
重度腎機能障害患者にはFTD・TPI配合剤をFTD換算量として30〜50mg/m2/日の投与量に減量することにより、特にFTD換算量として40mg/m2/日の投与量に減量することにより、安全性を維持しながら奏効を期待できる。
Claims (7)
- クレアチニンクリアランスが15mL/min以上29mL/min以下である患者における癌の治療剤であって、α,α,α−トリフルオロチミジン(FTD)と5−クロロ−6−[(2−イミノピロリジン−1−イル)メチル]ピリミジン−2,4(1H,3H)−ジオン塩酸塩をモル比1:0.5で含有する配合剤が、FTD換算量として30〜50mg/m2/日の用量を1日2〜4回に分割して前記患者に経口投与される、治療剤。
- FTD換算量として40mg/m2/日の用量を1日2回に分割して経口投与される、請求項1記載の癌の治療剤。
- 投与スケジュールが、1週あたり、5日間連続経口投与2日間休薬である、請求項1又は2記載の癌の治療剤。
- 投与スケジュールが、5日間連続経口投与2日間休薬を2回繰り返したのち14日間休薬である、請求項1〜3のいずれか1項に記載の癌の治療剤。
- 癌が、消化器癌又は乳癌である、請求項1〜4のいずれか1項に記載の癌の治療剤。
- 癌が、大腸癌である、請求項1〜5のいずれか1項に記載の癌の治療剤。
- 癌が、胃癌である、請求項1〜5のいずれか1項に記載の癌の治療剤。
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