JP5376758B2 - テガフールの投与に起因する消化器毒性を軽減する方法 - Google Patents
テガフールの投与に起因する消化器毒性を軽減する方法 Download PDFInfo
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- JP5376758B2 JP5376758B2 JP2006539166A JP2006539166A JP5376758B2 JP 5376758 B2 JP5376758 B2 JP 5376758B2 JP 2006539166 A JP2006539166 A JP 2006539166A JP 2006539166 A JP2006539166 A JP 2006539166A JP 5376758 B2 JP5376758 B2 JP 5376758B2
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- Prior art keywords
- tegafur
- administered
- pharmaceutically acceptable
- acceptable salt
- antitumor
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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Description
本発明は、消化器毒性を軽減するための、テガフール[5−フルオロ−1−[(RS)−テトラヒドロフラン−2−イル]ピリミジン−2,4−(1H,3H)−ジオン]の投与方法に関する。
米国特許第5,155,113号は、ある種のピリジン化合物が、5−フルオロウラシルおよび5−FUの誘導体の抗腫瘍効果の増強剤として使用され得ることを教示している。該ピリジン化合物は、生体内における5−FUの濃度を維持させる。不運にも、生体内において5−FUが長時間存在することは、口腔および消化管組織において炎症を引き起こし、そして5−FU単独の持続点滴静注でしばしば経験されるような下痢を誘発する傾向がある。
本発明は、テガフールの抗腫瘍効果を増強しかつこのような治療の必要がある患者における消化器毒性を軽減する方法であって、治療的に有効な量のテガフール、該抗腫瘍効果を増強するために有効な量のジヒドロピリミジンデヒドロゲナーゼ阻害剤、および消化器毒性を抑制するために有効な量のオキソン酸またはその薬学的に許容される塩を、空腹条件下で、該患者へ同時に投与することを包含する方法に関する。好ましくは、組成物の投与は、空腹条件下で1日2回であり、そしてジヒドロピリミジンデヒドロゲナーゼ阻害剤は、2,4−ジヒドロキシ−5−クロロピリジンである。組成物の2回の投与は、好ましくは6〜12時間隔てられ、そして空腹条件は、食事の少なくとも1時間前または1時間後で生じる。より好ましくは、空腹条件は、食事の少なくとも1時間前で生じる。2,4−ジヒドロキシ−5−クロロピリジンおよびオキソン酸またはその薬学的に許容される塩は、0.4:1のモル比で使用され得、好ましくは、テガフール、2,4−ジヒドロキシ−5−クロロピリジン、およびオキソン酸またはその薬学的に許容される塩は、(テガフール):(2,4−ジヒドロキシ−5−クロロピリジン):(オキソン酸またはその薬学的に許容される塩)=1:0.4:1のモル比で使用され、そして薬学的に許容される塩は、オキソン酸カリウムである。
本発明は、前記活性成分のバイオアベイラビリティーに対して食物のいかなる望まれない効果をも回避するために、空腹条件下で前記抗腫瘍組成物を投与することによって、治療的に有効な量のテガフールを含有する抗腫瘍組成物の抗腫瘍効果を増強させかつ前記抗腫瘍組成物の消化器系副作用を抑制する方法を提供する。
−FTは、優れた経口バイオアベイラビリティーを有する5−FUのプロドラッグである。それは、生体内で5−FUへ徐々に変換される。
(1)Mosteller式(N. Engl. J. Med. 1987 Oct 22; 317 (17): 1098 (letter) を参照のこと)
BSA(m2)=([身長(cm)×体重(kg)]/3600)1/2
(2)DuBoisおよびDuBois式(Arch. Int. Med. 1916 17: 863-71; J. Clin. Anesth. 1992; 4 (1): 4-10 を参照のこと)
(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)Haycock式(The Journal of Pediatrics 1978 93: 1 : 62-66を参照のこと)
BSA(m2)=0.024265×身長(cm)0.3964×体重(kg)0.5378
(4)GehanおよびGeorge式(Cancer Chemother. Rep. 1970 54: 225-35を参照のこと)
BSA(m2)=0.0235×身長(cm)0.42246×体重(kg)0.51456
(5)Boyd式(Minneapolis: University of Minnesota Press, 1935を参照のこと)
BSA(m2)=0.0003207×身長(cm)0.3×体重(g)(0.7285−(0.0188×LOG(g))
(6)藤本式(Nippon Eiseigaku Zasshi 1968;5:443-50を参照のこと)
BSA(m2)=88.83×身長(cm)0.663×体重(kg)0.444。
(1)S−1の食後、1日2回、経口投与
第I相試験を、IND #53,765下で米国で行った。これは35日試験であった(28日治療期間、7日休薬期間)。S−1を、総計16患者に、連続28日間、食後、1日2回、経口投与した。用量は、30mg/m2、35mg/m2、および40mg/m2であった。3患者を、用量を増加する前に各用量で試験するものとし、そして追加の10患者を、S−1の効果を完全に規定するために最大用量で治療するものとした。
S−1の日本での試験結果に基づいて、試験した第一用量は、欧州での、第I相試験において、食事後、1日2回、25mg/m2であった。この用量で治療した6患者において、用量制限毒性は発生しなかった。次いで、5患者を45mg/m2で治療した。主要な用量制限毒性として重篤な下痢を伴って、この用量が、MTDであると決定された。別の6患者を35mg/m2の用量で治療し、重篤な毒性は観察されなかった。40mg/m2、試験した最終用量での6患者において、重篤な下痢が再度観察された(主に、広範な前化学療法を受けた患者において)。広範な前化学療法を受けていない患者においてこの用量の安全性を評価するために、広範な前治療されていない別の5患者を含めた。
1日2回、25mg/m2のS−1での治療は、軽度の毒性を示した。1日2回、45mg/m2で、下痢(1患者においてグレード3、2患者においてグレード4)がDLTであった。他の重篤な毒性は、グレード4の嘔吐(1患者)、グレード3の食欲不振(2患者)、グレード3の疲労/倦怠感(2患者)およびグレード3の白血球減少症/好中球減少症(1患者)であった。1日2回、35mg/m2では、重篤な毒性は観察されなかった。40mg/m2で、下痢が、広範な前化学療法を受けた患者についてDLTであった:化学療法で重い前処置した3患者のうち、1患者はグレード3の、そして1患者はグレード4の下痢を有した。広範な前化学療法を受けなかった8患者においては、グレード4の下痢の1症例およびグレード3の倦怠感の1症例が報告された。したがって、1日2回45mg/m2が、広範な前化学療法処置無しの患者についてのMTD(DLTとして下痢)であった。前化学療法がない、または5−FUアジュバント化学療法のみを受けた、結腸・直腸癌および胃癌患者における今後のECSG/NDDO第II相試験のための推奨用量は、S−1の1日2回40mg/m2である。化学療法でより重い前処置を受けた患者に対するMTDは、1日2回の40mg/m2であり(DLTとして下痢)、このカテゴリーの患者の治療に対して、推奨用量は、S−1の1日2回の35mg/m2である。
PKパラメータに対する食物の影響を、S−1の35mg/m2の用量で試験した。17患者を登録させ、そしてクロスオーバー法で朝食後および朝食前の両方にS−1を投与した。患者の診断は、結腸・直腸癌(7例)、乳癌(3例)、胃癌(3例)およびその他(4例)であった。結果は、Oxoは、空腹条件においてより安定であることを示唆した(CA、即ち、シアヌル酸は、Oxoの不活性代謝物である)。このデータに基づいて、進行中の米国試験において、S−1を食事の少なくとも1時間前に投与する。
総計17患者が、インフォームドコンセント後、この薬物動態試験に参加した。全ての患者は、試験の2集団に対し無作為化され、そして35mg/m2でS−1を摂取した。系列Aでは、患者は、第0日目に朝食後に、第7日目に朝食無しで、S−1を摂取した。系列Bでは、患者は、第0日目に朝食無しで、第7日目に朝食後に、S−1を摂取した。血液を24時間サンプリングした。サンプルを、S−1摂取の前ならびに30分後、1時間後、2時間後、4時間後、8時間後、10時間後および24時間後に採取した。血液サンプルを、9mlのヘパリン化チューブに静脈穿刺により採取し、そして即座の処置のために氷上に移した。
テガフール、5FU、オキソン酸、シアヌル酸、およびCDHPについての薬物動態パラメータを、コンピュータプログラムWinNonLin(ver.1.5)で計算した。データを、非コンパートメントモデリング(non-compartment modeling)を使用して分析した。確立され得るパラメータは、次の通りであった:血漿中の最大観察濃度の時点(Tmax)、Tmaxに対応する血漿中の濃度(Cmax)、最終半減期(t1/2)、血漿中濃度時間(C−t)曲線下面積(AUCall)。
<テガフールの薬物動態>
母化合物、テガフールは、朝食無しで、より早くそのTmaxに到達した(表1)。Cmaxは、摂食群よりも空腹群においてより高かった。いずれの群においても、t1/2およびAUCallについて有意な差異は無かった。
5−FUのTmaxは、朝食無しで、より早く到達した。いずれの群においても、t1/2、CmaxおよびAUCallについて有意な差異は無かった。
CDHPのTmaxもまた、朝食無しで、より早く到達した。いずれの群においても、t1/2、CmaxおよびAUCallについて有意な差異は無かった。
オキソン酸のTmaxは、朝食無しで有意により早く到達した。対応するCmaxは、朝食無しで有意により高かった。t1/2は、各群において有意な差異はなかった。OxoのAUCallは、摂食群よりも空腹群において高かった。
シアヌル酸は、朝食無しで、より早いTmaxを示した。対応するCmaxは、いずれの群においても有意な差異はなかった。また、t 1/2は、いずれの群においても有意な差異はなかった。シアヌル酸のAUCallは、空腹群と比較して摂食群においてより高い値を示した。
本発明によれば、食後投与の治療スケジュールと比較して、軽減された消化器毒性および下痢、より低い下痢の発生率に起因するより長期間の治療等の優れた利点が、(A)治療的に有効な量のテガフール、(B)該抗腫瘍効果を増強するために有効な量のジヒドロピリミジンデヒドロゲナーゼ阻害剤、および(C)消化器毒性を抑制するために有効な量のオキソン酸またはその薬学的に許容される塩を、空腹条件下で、患者へ同時に投与することによって達成される。
Claims (20)
- 癌患者を治療する抗腫瘍組成物であって、該癌が5−フルオロウラシル療法に感受性があり、治療的に有効な量のテガフール、テガフールの抗腫瘍効果を増強するために有効な量の2,4−ジヒドロキシ−5−クロロピリジン、および消化器毒性を抑制するために有効な量のオキソン酸またはその薬学的に許容される塩を含み、空腹条件下で投与され、該空腹条件が食事の少なくとも1時間前であることを特徴とする、抗腫瘍組成物。
- 前記組成物が、空腹条件下で1日2回投与されるものである、請求項1に記載の抗腫瘍組成物。
- 前記組成物の2回の投与が6〜12時間隔てられる、請求項2に記載の抗腫瘍組成物。
- 前記2,4−ジヒドロキシ−5−クロロピリジン(B)および前記オキソン酸またはその薬学的に許容される塩(C)のモル比が、(B):(C)=0.4:1である、請求項1乃至3のいずれかに記載の抗腫瘍組成物。
- 前記薬学的に許容される塩がオキソン酸カリウムである、請求項1乃至4のいずれかに記載の抗腫瘍組成物。
- 前記テガフール、前記2,4−ジヒドロキシ−5−クロロピリジン、および前記オキソン酸またはその薬学的に許容される塩のモル比が、(テガフール):(2,4−ジヒドロキシ−5−クロロピリジン):(オキソン酸またはその薬学的に許容される塩)=1:0.4:1である、請求項1乃至5のいずれかに記載の抗腫瘍組成物。
- 前記テガフールの用量が20mg/m2〜45mg/m2となるように含まれており、且つ1日2回投与される、請求項1乃至6のいずれかに記載の抗腫瘍組成物。
- シスプラチン、1,3−ビス(2−クロロエチル)−1−ニトロソウレア、ドセタキセル、ドキソルビシン、エピルビシン、エトポシド、メトトレキサート、マイトマイシン、ゲムシタビン、カルボプラチン、ゲフィチニブ、ペメトレキセド、アバスチン、セツキシマブおよびパクリタキセルからなる群から選択される化学療法剤と組み合わせて使用される、請求項1乃至7のいずれかに記載の抗腫瘍組成物。
- シスプラチンの静脈内投与と組み合わせて使用される、請求項1乃至7のいずれかに記載の抗腫瘍組成物。
- 前記シスプラチンが1日当たり50〜80mg/m2の用量で投与される、請求項9に記載の抗腫瘍組成物。
- 前記抗腫瘍組成物は空腹条件下で投与されるべきであることを該患者に注意する表示を備えるパッケージに収容されている、請求項1乃至10のいずれかに記載の抗腫瘍組成物。
- 癌患者に対するテガフールの投与によって引き起こされる炎症および消化器毒性を抑制するための薬学的組成物であって、消化器毒性を抑制するために有効な量のオキソン酸またはその薬学的に許容される塩を含み、空腹条件下で該テガフールと同時に投与され、該空腹条件が食事の少なくとも1時間前であることを特徴とする、薬学的組成物。
- 前記組成物が、空腹条件下で1日2回投与されるものである、請求項12に記載の薬学的組成物。
- さらにテガフールの抗腫瘍効果を増強するために有効な量の2,4−ジヒドロキシ−5−クロロピリジンを含む、請求項12または13に記載の薬学的組成物。
- テガフールでの治療を受ける患者の消化管におけるオキソン酸の分解を減少させるための薬学的組成物であって、治療的に有効な量のテガフール、および消化器毒性を抑制するために有効な量のオキソン酸またはその薬学的に許容される塩を含み、空腹条件下で投与され、該空腹条件が食事の少なくとも1時間前であることを特徴とする、薬学的組成物。
- 前記組成物が、空腹条件下で1日2回投与されるものである、請求項15に記載の薬学的組成物。
- さらにテガフールの抗腫瘍効果を増強するために有効な量の2,4−ジヒドロキシ−5−クロロピリジンを含む、請求項15または16に記載の薬学的組成物。
- 癌患者を治療するためのキットであって、1日2回の投与に好適な投与量の、テガフール、2,4−ジヒドロキシ−5−クロロピリジン、オキソン酸またはその薬学的に許容される塩を含み、該テガフール、該2,4−ジヒドロキシ−5−クロロピリジン、および該オキソン酸またはその薬学的に許容される塩が空腹条件下で同時に投与されることが決められており、該空腹条件が食事の少なくとも1時間前である、キット。
- さらに、シスプラチン、1,3−ビス(2−クロロエチル)−1−ニトロソウレア、ドセタキセル、ドキソルビシン、エピルビシン、エトポシド、メトトレキサート、マイトマイシン、ゲムシタビン、カルボプラチン、ゲフィチニブ、ペメトレキセド、アバスチン、セツキシマブおよびパクリタキセルからなる群から選択される抗腫瘍剤を含む、請求項18に記載のキット。
- さらに、テガフール、2,4−ジヒドロキシ−5−クロロピリジン、およびオキソン酸またはその薬学的に許容される塩が空腹条件下で同時に投与されるべきであることを注意する表示を備えている、請求項18または19に記載のキット。
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EP3122354B1 (en) | 2014-03-28 | 2022-06-15 | Universita' degli Studi di Genova | Tyrosine kinase inhibitors for use in a method of treating cancer in association with a reduced caloric intake |
WO2016175324A1 (ja) * | 2015-04-30 | 2016-11-03 | 大鵬薬品工業株式会社 | 抗腫瘍剤の副作用軽減剤 |
JP6439761B2 (ja) * | 2016-08-09 | 2018-12-19 | トヨタ自動車株式会社 | NOx吸蔵還元触媒の製造方法 |
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US3635946A (en) * | 1969-07-22 | 1972-01-18 | Solomon Aronovich Giller | N1-(2'-furanidyl)-derivatives of 5-substituted uracils |
DK175432B1 (da) * | 1984-10-30 | 2004-10-18 | Otsuka Pharma Co Ltd | Middel til forögelse af anticancervirkningen af anticancerforbindelser |
US5968914A (en) * | 1987-10-28 | 1999-10-19 | Pro-Neuron, Inc. | Treatment of chemotherapeutic agent and antiviral agent toxicity with acylated pyrimidine nucleosides |
NL194430C (nl) * | 1989-01-05 | 2002-04-04 | Otsuka Pharma Co Ltd | Niet-injecteerbaar farmaceutisch preparaat met anti-kankerwerking. |
ATE173165T1 (de) * | 1991-05-27 | 1998-11-15 | Taiho Pharmaceutical Co Ltd | Zusammensetzung, verfahren und instrument zur potenzierung der antitumoraktivität und zur behandlung von tumoren |
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- 2005-04-27 WO PCT/JP2005/008450 patent/WO2005105086A1/en active Application Filing
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- 2005-04-27 RU RU2006142101/14A patent/RU2348409C2/ru active
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WO2005105086A1 (en) | 2005-11-10 |
AU2005237364B2 (en) | 2010-07-08 |
ATE540679T1 (de) | 2012-01-15 |
JP2007534634A (ja) | 2007-11-29 |
RS52217B (en) | 2012-10-31 |
PT1750703E (pt) | 2012-02-23 |
ES2378072T3 (es) | 2012-04-04 |
CY2012014I1 (el) | 2016-04-13 |
EP1750703A1 (en) | 2007-02-14 |
PL1750703T3 (pl) | 2012-05-31 |
AU2005237364A1 (en) | 2005-11-10 |
US20080166427A1 (en) | 2008-07-10 |
EP1750703B1 (en) | 2012-01-11 |
RU2006142101A (ru) | 2008-06-20 |
EP1750703A4 (en) | 2008-02-27 |
RU2348409C2 (ru) | 2009-03-10 |
ME01335B (me) | 2013-12-20 |
CY1112451T1 (el) | 2015-12-09 |
CY2012014I2 (el) | 2016-04-13 |
DK1750703T3 (da) | 2012-05-07 |
SI1750703T1 (sl) | 2012-02-29 |
HRP20120293T1 (hr) | 2012-04-30 |
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