Graff Jochen, von Hentig Nils, Misselwitz Frank, Kubitza Dagmar, Becka Michael, Breddin Hans-Klaus, Harder Sebastian
Pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology, University Hospital, Frankfurt/Main, Theodor Stern Kai 7, D-60590 Frankfurt am Main, Germany.
J Clin Pharmacol. 2007 Nov;47(11):1398-407. doi: 10.1177/0091270007302952. Epub 2007 Sep 14.
Rivaroxaban (BAY 59-7939) is an oral, direct factor Xa inhibitor in advanced development. This study was undertaken to investigate its effects on thrombin generation. In this placebo-controlled, randomized, crossover study, 12 healthy subjects received rivaroxaban (single 5- or 30-mg dose) or placebo. Thrombin generation was investigated by measuring the endogenous thrombin potential and prothrombinase-induced clotting time. Maximal effect of rivaroxaban was observed 2 hours after drug administration: prothrombinase-induced clotting time was prolonged 1.8 and 2.3 times baseline after rivaroxaban 5 and 30 mg, respectively. Collagen-induced endogenous thrombin potential was reduced by approximately 80% and approximately 90% compared with baseline after rivaroxaban 5 and 30 mg, respectively, and tissue factor-induced endogenous thrombin potential was reduced by approximately 40% (5 mg) and approximately 65% (30 mg), respectively. Thrombin generation remained inhibited for 24 hours. There was a close correlation between plasma concentration of rivaroxaban and prolongation of prothrombinase-induced clotting time and reduction in endogenous thrombin potential. Rivaroxaban strongly inhibits platelet-induced thrombin generation, after activation of either platelets or the coagulation pathway, even in the presence of minimal factor Xa inhibition in plasma.
利伐沙班（BAY 59 - 7939）是一种处于后期研发阶段的口服直接Xa因子抑制剂。本研究旨在探究其对凝血酶生成的影响。在这项安慰剂对照、随机、交叉研究中，12名健康受试者接受了利伐沙班（单次5毫克或30毫克剂量）或安慰剂。通过测量内源性凝血酶潜力和凝血酶原酶诱导的凝血时间来研究凝血酶生成情况。给药后2小时观察到利伐沙班的最大效应：利伐沙班5毫克和30毫克给药后，凝血酶原酶诱导的凝血时间分别延长至基线的1.8倍和2.3倍。与基线相比，利伐沙班5毫克和30毫克给药后，胶原诱导的内源性凝血酶潜力分别降低约80%和约90%，组织因子诱导的内源性凝血酶潜力分别降低约40%（5毫克）和约65%（30毫克）。凝血酶生成抑制作用持续24小时。利伐沙班血浆浓度与凝血酶原酶诱导的凝血时间延长及内源性凝血酶潜力降低之间存在密切相关性。即使血浆中Xa因子抑制作用极小，利伐沙班在激活血小板或凝血途径后，仍能强烈抑制血小板诱导的凝血酶生成。
