従来，臨床には， 「薬のさじ加減」 ということばが ある．これは医師が薬の用量−反応関係を経験的に 取得し，個々の患者に対し適切な薬物選択と用量設 定を行うことを意味する．しかし，この方法は普遍 性に乏しく，black box が大きいため，危険性も潜 んでいる．近年，薬の適正使用が唱えられ，各患者 に応じた個別化治療を行うことが，有効性のみなら ず安全性のうえで欠かせないとされる．その手段と して，各患者における生体内での薬物の動きと効果 を理解することは重要である． 薬物動態学とは 薬物の生体内での流れ・運命を薬物動態という． 生体内に薬を投与すると，吸収・分布・代謝・排泄 を経て除去される．この過程で薬の一部が作用部位 に到達し，薬物受容体と結合し，薬理効果が出現す る．体液中の薬物濃度の時間的推移を速度論的に解 析し，薬物の生体内動態を研究する領域を薬物動態 学 （pharmacokinetics） と呼ぶ．一方，薬物が受容体 と結合し，薬理効果が出現するまでの領域を薬力学 （pharmacodynamics） と呼び，薬物動態学と作用部 位における薬物濃度によって密接にかかわってい る．個々の薬物反応には年齢，性別，遺伝的差異， 環境因子，食事，生活習慣，基礎疾患，併用薬など 様々な因子が薬物動態および薬力学の双方を介し て影響する． 薬物血中濃度モニタリング 抗不整脈薬は強力な薬理作用を有している反面， 重篤な副作用も合わせもっており，単なるさじ加減 では管理が難しい面がある．このため抗不整脈薬の 分野では，ジゴキシン，キニジンに代表されるよ うに古くから薬物動態の検討が行われ，薬物血中 濃度モニタリング （Therapeutic Drug Monitoring : TDM） を治療に応用してきた 1） ． 尿中未変化体排泄率の高い （腎排泄型） 薬は，腎機 能の変化で容易に血中濃度が変わる．一方，肝代謝 型の薬は代謝酵素活性の個人差に左右される．チト クロム P450 （CYP） 2D6 で代謝されるアプリンジン やプロパフェノン，ベプリジルは代謝能の飽和現象 から，用量と血中濃度は非線形関係にある．また， 複雑な薬物動態を特徴とするアミオダロンやベプリジ ルは， 同じ用量であっても個人あるいは投与期間によ り血中濃度は異なるため，TDM が必要とされよう． べプリジルは日本でのみ抗不整脈薬として使用さ れており，日本人における血中濃度と抗不整脈効果 や安全性に関する報告が出されている 2）-6） ．これ らのデータを基に， ベプリジルの治療域濃度は 250-800 ng/ml とされた．また，そのクリアランスは低 体重や加齢とともに低下することが示されており， 高齢者での低用量化が求められる． 7）, 8） P-糖蛋白の問題 P-糖 蛋 白 は， ア デ ノ シ ン 三 リ ン 酸 （adenosine triphosphate : ATP） に依存して有害物質 （陽イオン 東京女子医科大学循環器内科 志賀 剛

No abstract

Dabigatran etexilate is an oral low-molecular-weight direct thrombin inhibitor. Following oral administration, dabigatran etexilate is rapidly converted to its active form, dabigatran. The authors investigated the absorption, distribution, and elimination of a single 150-mg dose capsule formulation of dabigatran etexilate in healthy volunteers and patients undergoing total hip replacement. In an open-label, 3-way crossover study, dabigatran etexilate was administered to 18 male volunteers in the fasted state, after administration of food and with coadministration of the proton pump inhibitor, pantoprazole. In a subsequent multicenter, open-label study, 59 patients received a single dose of dabigatran etexilate, administered 1 to 3 hours following total hip replacement. In healthy volunteers, food had no effect on the extent of absorption of dabigatran etexilate, although there was reduced interindividual variability for dabigatran maximum plasma concentration and AUC(0-infinity). A decrease in the mean dabigatran AUC(0-infinity) (904 to 705 ng*h/mL) occurred with coadministration of pantoprazole. In patients undergoing total hip replacement, immediate onset of absorption was seen with the maximum plasma concentration of dabigatran occurring after 6 hours. The AUC(0-24) of dabigatran was 88% of the steady-state AUC using a preliminary tablet formulation and 106% of that seen in the healthy volunteer study. Compared with healthy volunteers, the postoperative profile was flattened with delayed peak concentrations. In summary, administration of the dabigatran etexilate capsule with food has no effect on the extent of dabigatran absorption, with a moderate decrease when coadministered with pantoprazole. Adequate plasma concentrations of dabigatran were seen with early postoperative administration of the dabigatran etexilate capsule. These pharmacokinetic characteristics confirm the suitability of this oral solid dosage form for use in future clinical trials.

No abstract

USATo cite this article: Eriksson BI, Dahl OE, Ahnfelt L, Kä lebo P, Stangier J, Nehmiz G, Hermansson K, Kohlbrenner V. Dose escalating safety study of a new oral direct thrombin inhibitor, dabigatran etexilate, in patients undergoing total hip replacement: BISTRO I. (12.5, 25, 50, 100, 150, 200 and 300 mg twice daily or 150 and 300 mg once daily) administered 4-8 h after surgery, for 6-10 days. Dose escalation was based on clinical and pharmacokinetic data. The primary safety outcome was major bleeding. The primary efficacy outcome included venographic deep vein thrombosis (DVT), symptomatic DVT and pulmonary embolism, during the treatment period. Results: No major bleeding event was observed in any group, but two patients at the highest dose (300 mg twice daily) suffered bleeding from multiple sites associated with reduced renal clearance and prolonged pharmacodynamic (PD) parameters. A dose-response was demonstrated for minor bleeding events. Of the 289 treated patients, 225 patients had evaluable venograms. The overall incidence of DVT was 12.4% (28/225 patients). There was no consistent relationship between the dose and incidence of DVT, the highest incidence in any group being 20.8% (5/24 patients). The lowest dose (12.5 mg twice daily) showed a high rate of proximal DVT [12.5% (3/24)] and no increase in PD parameters. Peak and trough plasma concentrations, area under the dabigatran plasma concentration-time curve and PD parameters also increased in proportion with the dose. Higher dabigatran plasma concentrations were associated with lower DVT rates. Approximately 20% of the patients had low plasma concentrations after the first dose suggesting further optimization of the preliminary tablet formulation is required. Conclusions: Dabigatran etexilate demonstrates an acceptable safety profile, with a therapeutic window above 12.5 mg and below 300 mg twice daily. The low number of VTE events within each treatment group indicates a satisfactory antithrombotic potential, although the study was not powered for an efficacy analysis. Additional studies are ongoing to optimize oral absorption and the efficacy/safety balance.