Kubitza Dagmar, Becka Michael, Mück Wolfgang, Krätzschmar Jöern
Clinical Sciences, Bayer HealthCare, Wuppertal, Germany.
Br J Clin Pharmacol. 2014 Aug;78(2):353-63. doi: 10.1111/bcp.12349.
This study investigated relevant pharmacodynamic and pharmacokinetic parameters during the transition from warfarin to rivaroxaban in healthy male subjects.
Ninety-six healthy men were randomized into the following three groups: warfarin [international normalized ratio (INR) 2.0-3.0] transitioned to rivaroxaban 20 mg once daily (od; group A); warfarin (INR 2.0-3.0) followed by placebo od (group B); and rivaroxaban alone 20 mg od (group C) for 4 days. Anti-factor Xa activity, inhibition of factor Xa activity, prothrombin time (PT), activated partial thromboplastin time, HepTest, prothrombinase-induced clotting time, factor VIIa activity, factor IIa activity, endogenous thrombin potential and pharmacokinetics were measured.
An additive effect was observed on the PT and PT/INR during the initial transition period. The mean maximal prolongation of PT was 4.39-fold [coefficient of variation (CV) 18.03%; range 3.39-6.50] of the baseline value in group A, compared with 1.88-fold (CV 10.35%; range 1.53-2.21) in group B and 1.57-fold (CV 9.98%; range 1.37-2.09) in group C. Rivaroxaban had minimal influence on the PT/INR at trough levels. Inhibition of factor Xa activity, activated partial thromboplastin time and endogenous thrombin potential were also enhanced, but to a lesser extent. In contrast, the effects of rivaroxaban on anti-factor Xa activity, HepTest and prothrombinase-induced clotting time were not affected by pretreatment with warfarin.
Changes in pharmacodynamics during the transition from warfarin to rivaroxaban vary depending on the test used. A supra-additive effect on PT/INR is expected during the initial period of transition, but pretreatment with warfarin does not influence the effect of rivaroxaban on anti-factor Xa activity.
本研究调查了健康男性受试者从华法林转换为利伐沙班期间的相关药效学和药代动力学参数。
96名健康男性被随机分为以下三组：华法林（国际标准化比值[INR] 2.0 - 3.0）转换为利伐沙班20毫克每日一次（od；A组）；华法林（INR 2.0 - 3.0）后接安慰剂od（B组）；以及单独使用利伐沙班20毫克od（C组），共4天。测量抗Xa因子活性、Xa因子活性抑制率、凝血酶原时间（PT）、活化部分凝血活酶时间、HepTest、凝血酶原酶诱导的凝血时间、VIIa因子活性、IIa因子活性、内源性凝血酶潜力和药代动力学。
在初始转换期观察到PT和PT/INR有相加效应。A组PT的平均最大延长倍数为基线值的4.39倍[变异系数（CV）18.03%；范围3.39 - 6.50]，相比之下，B组为1.88倍（CV 10.35%；范围1.53 - 2.21），C组为1.57倍（CV 9.98%；范围1.37 - 2.09）。利伐沙班在谷浓度时对PT/INR影响最小。Xa因子活性抑制率、活化部分凝血活酶时间和内源性凝血酶潜力也有所增强，但程度较小。相比之下，利伐沙班对抗Xa因子活性、HepTest和凝血酶原酶诱导的凝血时间的影响不受华法林预处理的影响。
从华法林转换为利伐沙班期间药效学的变化因所使用的检测方法而异。在转换初期预计对PT/INR有超相加效应，但华法林预处理不影响利伐沙班对抗Xa因子活性的作用。
