Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany.
Curr Med Res Opin. 2012 Feb;28(2):195-201. doi: 10.1185/03007995.2011.654109. Epub 2012 Jan 23.
Dabigatran is a new oral anticoagulant recently approved for the prevention of stroke or systemic embolism in patients with atrial fibrillation (AF). Based on its pharmacokinetic profile, dabigatran is dosed twice daily. This analysis provides a quantitative rationale for the selection of the dose regimen in this population.
The pharmacokinetic profile of dabigatran was simulated for AF patients given a total daily dose of 300 mg, either once or twice daily. Simulations were based on a population pharmacokinetic model supplemented with data collected from 9522 patients enrolled in a pivotal phase III study (RE-LY).
The typical RE-LY patient (male, 72 years old, Caucasian, weight 80 kg, creatinine clearance 68.64 mL/min) treated with dabigatran 150 mg twice daily showed less than two-fold difference between peak-trough plasma levels compared with a five-fold difference when the same total dose (300 mg) was administered once daily. For patients who miss or delay taking one scheduled dabigatran dose, twice daily dosing maintained adequate minimum trough concentrations better than once daily dosing. Pharmacokinetic data collected from a phase II study and RE-LY were consistent with the simulation results. The study did not access comparative efficacy and bleeding data for once versus twice daily dosing.
Pharmacokinetic simulations show that a twice daily regimen in patients with AF minimizes daily fluctuations in plasma concentrations of dabigatran and can maintain trough concentrations sufficient to prevent the development of thrombi while at the same time minimizing the risk of bleeding due to supratherapeutic peak plasma concentrations. The efficacy and safety of this dosing regimen is supported by clinical data from the RE-LY trial.
达比加群酯是一种新型的口服抗凝药物，最近被批准用于预防房颤（AF）患者的中风或全身性栓塞。基于其药代动力学特征，达比加群酯每天给药两次。本分析为该人群选择剂量方案提供了定量依据。
根据关键性 III 期研究（RE-LY）中纳入的 9522 例患者的数据，对接受 300mg 总日剂量、每日一次或两次的 AF 患者的达比加群酯药代动力学特征进行模拟。模拟基于群体药代动力学模型进行补充。
RE-LY 中的典型患者（男性，72 岁，白种人，体重 80kg，肌酐清除率 68.64mL/min）接受 150mg 达比加群酯每日两次治疗时，与每日一次给予相同总剂量（300mg）相比，峰谷血浆水平差异不到两倍。对于错过或延迟服用一次预定剂量达比加群酯的患者，每日两次给药比每日一次给药能更好地维持足够的最低谷浓度。来自 II 期研究和 RE-LY 的药代动力学数据与模拟结果一致。本研究未评估每日一次与每日两次给药的比较疗效和出血数据。
药代动力学模拟表明，AF 患者每日两次的给药方案使达比加群酯的血浆浓度波动最小化，并能维持足够的谷浓度以预防血栓形成，同时最大限度地降低因超治疗性血浆峰浓度而导致出血的风险。RE-LY 试验的临床数据支持该给药方案的疗效和安全性。
