Boehringer Ingelheim Pharma GmbH & Co. KG, Translational Medicine, D-88397 Biberach an der Riss, Germany.
J Clin Pharmacol. 2012 Sep;52(9):1373-8. doi: 10.1177/0091270011417716. Epub 2011 Sep 28.
Dabigatran, administered orally as the prodrug dabigatran etexilate (DE), is a direct thrombin inhibitor shown to be effective in the prevention of stroke and systemic embolism in patients with atrial fibrillation (AF). The aim of this analysis was to derive a modeling and simulation-based dose and dosing regimen for AF patients with severe renal failure who could potentially benefit from the use of DE. The exposure was simulated for AF patients with severe renal impairment for several combinations of doses (75, 110, 150 mg) and posologies (BID, QD, Q2D). Simulations were based on a population pharmacokinetic model derived from data from 9522 patients from the pivotal phase III study (RE-LY). Atrial fibrillation patients with a creatinine clearance (CRCL) of <30 to ≥15 mL/min treated with a dose of 75 mg DE BID have target plasma level and exposure data largely within the concentration range proven to be safe and effective in AF patients with CRCL >30 mL/min receiving 150 mg BID. This dosing algorithm was also confirmed and supported by the United States Food and Drug Administration Clinical Pharmacology Division using their model based on the data from the dedicated renal impairment study and taking into account the safety and efficacy information from RE-LY.
达比加群酯（DE）经口服给药，作为前体药物，是一种直接凝血酶抑制剂，已被证明可有效预防房颤（AF）患者的中风和全身性栓塞。本分析旨在为可能受益于 DE 治疗的严重肾功能衰竭的 AF 患者，推导一种基于建模和模拟的剂量和给药方案。针对几种剂量（75、110、150mg）和给药方案（BID、QD、Q2D）组合，对严重肾功能损害的 AF 患者进行了暴露模拟。模拟基于从关键性 III 期研究（RE-LY）中 9522 名患者的数据推导的群体药代动力学模型。对于肌酐清除率（CRCL）<30 至≥15 mL/min 的 AF 患者，给予 75mg DE BID 剂量，其目标血浆水平和暴露数据主要在 CRCL>30 mL/min 的接受 150mg BID 治疗的 AF 患者中已证明安全有效的浓度范围内。美国食品和药物管理局临床药理学分部也使用其基于专门的肾功能不全研究数据并考虑到 RE-LY 中的安全性和疗效信息的模型，对该给药方案进行了确认和支持。
