Daiichi Sankyo Pharma Development, 399 Thornall St., Edison, NJ 08837, USA.
Thromb Haemost. 2012 May;107(5):925-36. doi: 10.1160/TH11-08-0566. Epub 2012 Mar 8.
Edoxaban is a novel, orally available, highly specific direct inhibitor of factor Xa and is currently being developed for the treatment and prevention of venous thromboembolism and prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF). The objectives of the present analyses were to characterise edoxaban population pharmacokinetics (PPK) and identify potential intrinsic and extrinsic factors affecting variability in edoxaban exposure, determine if there are relationships between edoxaban pharmacokinetics or biomarkers and the risk of bleeding in patients with NVAF using an exposure-response model, and to use the PPK and exposure-response model to support dose selection for a phase III trial of edoxaban in patients with NVAF. PPK analysis of data from 1,281 edoxaban-dosed subjects with intrinsic factors such as renal impairment or NVAF and extrinsic factors such as concomitant medications revealed significant effects of renal impairment and concomitant strong P-glycoprotein (P-gp) inhibitors on the pharmacokinetics of edoxaban. Exposure-response analysis found that in patients with NVAF, the incidence of bleeding events increased significantly with increasing edoxaban exposure, with steady-state minimum concentration (Cmin,ss) showing the strongest association. Clinical trial simulations of bleeding incidence were used to select 30 mg and 60 mg once-daily edoxaban with 50% dose reductions for patients with moderate renal impairment or receiving concomitant strong P-gp inhibitors as the treatment regimens in the ENGAGE AF-TIMI 48 (NCT00781391) trial.
依度沙班是一种新型、口服、高度特异的直接因子 Xa 抑制剂，目前正在开发用于治疗和预防静脉血栓栓塞症，以及预防非瓣膜性心房颤动（NVAF）患者的中风和全身性栓塞。本分析的目的是描述依度沙班的群体药代动力学（PPK），并确定影响依度沙班暴露变异性的潜在内在和外在因素，确定依度沙班药代动力学或生物标志物与 NVAF 患者出血风险之间是否存在关系，以及使用暴露-反应模型来支持依度沙班在 NVAF 患者中的 III 期试验的剂量选择。对 1281 例有内在因素（如肾功能不全或 NVAF）和外在因素（如合并用药）的依度沙班给药受试者的数据进行 PPK 分析，结果显示肾功能不全和合并强 P-糖蛋白（P-gp）抑制剂对依度沙班的药代动力学有显著影响。暴露-反应分析发现，在 NVAF 患者中，随着依度沙班暴露量的增加，出血事件的发生率显著增加，稳态最小浓度（Cmin,ss）与出血事件的相关性最强。出血发生率的临床试验模拟用于选择 30mg 和 60mg 每日一次的依度沙班，对于中度肾功能不全的患者或接受合并强 P-gp 抑制剂治疗的患者，将剂量减少 50%，作为 ENGAGE AF-TIMI 48（NCT00781391）试验的治疗方案。
