Effects of the oral, direct factor xa inhibitor rivaroxaban on platelet-induced thrombin generation and prothrombinase activity.
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.
Graff
Jochen
J
Pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology, University Hospital, Frankfurt/Main, Theodor Stern Kai 7, D-60590 Frankfurt am Main, Germany. graff@em.uni-frankfurt.de
von Hentig
Nils
N
Misselwitz
Frank
F
Kubitza
Dagmar
D
Becka
Michael
M
Breddin
Hans-Klaus
HK
Harder
Sebastian
S
D000284:Administration, Oral; D000328:Adult; D000925:Anticoagulants / Q000493:pharmacokinetics*; D001777:Blood Coagulation / Q000187:drug effects; D001792:Blood Platelets / Q000166:cytology / Q000201:enzymology; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D015951:Factor Xa / Q000032:analysis; D065427:Factor Xa Inhibitors; D006801:Humans; D008297:Male; D009025:Morpholines / Q000493:pharmacokinetics*; D000069552:Rivaroxaban; D013876:Thiophenes / Q000493:pharmacokinetics*; D013917:Thrombin / Q000032:analysis; D013918:Thrombin Time; D013925:Thromboplastin / Q000032:analysis; D013997:Time Factors
D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D009025:Morpholines; D013876:Thiophenes; D013925:Thromboplastin; D000069552:Rivaroxaban; D013917:Thrombin; D015951:Factor Xa