Division of Clinical Sciences, St Georges University of London, UK.
Drugs. 2011 Aug 20;71(12):1503-26. doi: 10.2165/11595540-000000000-00000.
Edoxaban is an oral direct factor Xa inhibitor that is currently undergoing investigation in phase III clinical trials for the prevention of stroke in patients with atrial fibrillation (AF) and for the prevention and treatment of venous thromboembolic events (VTE). Factor Xa is an attractive target for anticoagulant treatment, as it is the primary and rate-limiting source of amplification in the coagulation cascade. Edoxaban is a competitive inhibitor of factor Xa and has >10 000-fold greater selectivity for factor Xa relative to thrombin. In phase I clinical trials, the anticoagulant effects of edoxaban included dose-dependent increases in activated partial thromboplastin time and prothrombin time following single edoxaban doses of 10-150 mg and after multiple ascending doses (60 mg twice daily, 90 mg daily and 120 mg daily). The anticoagulant effects of edoxaban were rapid in onset (time to peak plasma concentration 1-2 hours) and sustained for up to 24 hours. Prolongation of bleeding time in 8% of subjects was >9.5 minutes (none of which appeared to be clinically significant) 2 hours after initial dosing, and was independent of edoxaban dose, formulation or dietary state. In general, plasma edoxaban concentrations were linearly correlated with coagulation parameters. Phase II clinical trials in patients with AF and VTE suggest that the edoxaban 30 mg once-daily and 60 mg once-daily regimens had a similar or better safety profile compared with dose-adjusted warfarin (international normalized ratio 2.0-3.0) in terms of bleeding events, and that edoxaban was not associated with hepatotoxicity. In addition, edoxaban was associated with statistically significant dose-dependent reductions in VTE after orthopaedic surgery compared with placebo or dalteparin sodium. Further clinical investigation of the efficacy and safety of once-daily edoxaban is being conducted in phase III clinical trials in comparison with warfarin in patients with AF in the phase III ENGAGE AF-TIMI 48 trial (NCT00781391), and in comparison with low-molecular weight heparin/warfarin in the prevention of recurrent VTE in patients with symptomatic deep vein thrombosis and/or pulmonary embolism in the HOKUSAI VTE trial (NCT00986154).
依度沙班是一种口服直接 Xa 因子抑制剂，目前正在进行 III 期临床试验，以预防房颤（AF）患者的中风和预防及治疗静脉血栓栓塞事件（VTE）。Xa 因子是抗凝治疗的一个有吸引力的靶点，因为它是凝血级联反应中的主要和限速来源。依度沙班是 Xa 因子的竞争性抑制剂，相对于凝血酶，其对 Xa 因子的选择性高 10000 倍以上。在 I 期临床试验中，依度沙班的抗凝作用包括单次依度沙班剂量为 10-150mg 后，以及多次递增剂量（60mg 每日两次、90mg 每日一次和 120mg 每日一次）后，激活部分凝血活酶时间和凝血酶原时间呈剂量依赖性增加。依度沙班的抗凝作用起效迅速（达峰血浆浓度时间为 1-2 小时），可持续 24 小时。初始给药后 2 小时，8%的受试者的出血时间延长超过 9.5 分钟（均无临床意义），且与依度沙班剂量、剂型或饮食状态无关。一般来说，血浆依度沙班浓度与凝血参数呈线性相关。AF 和 VTE 患者的 II 期临床试验表明，与调整剂量的华法林（国际标准化比值 2.0-3.0）相比，依度沙班 30mg 每日一次和 60mg 每日一次方案在出血事件方面具有相似或更好的安全性，并且依度沙班与肝毒性无关。此外，与安慰剂或达肝素钠相比，依度沙班可显著降低骨科手术后 VTE 的发生率，且呈剂量依赖性。在 ENGAGE AF-TIMI 48 试验（NCT00781391）中，正在进行 III 期临床试验，比较依度沙班与华法林在 AF 患者中的疗效和安全性，在 HOKUSAI VTE 试验（NCT00986154）中，比较依度沙班与低分子肝素/华法林在有症状深静脉血栓形成和/或肺栓塞患者中的预防复发性 VTE 的疗效和安全性，进一步研究依度沙班的疗效和安全性。
