Effects of the Oral, Direct Factor Xa Inhibitor Rivaroxaban on Platelet‐Induced Thrombin Generation and Prothrombinase Activity<sup>1</sup>

Journal of Clinical Pharmacology - Tập 47 Số 11 - Trang 1398-1407 - 2007
Jochen Graff1, Nils von Hentig1, Frank Misselwitz2, Dagmar Kubitza2, Michael Becka2, Hans‐Klaus Breddin3, Sebastian Harder1
1Pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, University Hospital, Frankfurt am Main, Germany
2Bayer HealthCare, Wuppertal, Germany
3International Institute for Thrombosis and Vascular Diseases, Frankfurt am Main, Germany.

Tóm tắt

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 ∼80% and ∼90% compared with baseline after rivaroxaban 5 and 30 mg, respectively, and tissue factor‐induced endogenous thrombin potential was reduced by ∼40% (5 mg) and ∼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.

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Tài liệu tham khảo

10.1161/01.ATV.0000046238.23903.FC

Mann KG, 1998, The role of the tissue factor pathway in initiation of coagulation, Blood Coagul Fibrinolysis, 9, S3

10.1097/00062752-200009000-00003

10.1046/j.1538-7836.2003.00254.x

10.1016/S0049-3848(02)00080-4

10.1159/000073570

10.1160/TH04-01-0047

10.1111/j.1538-7836.2005.01166.x

10.1074/jbc.M009230200

10.1074/jbc.M909960199

10.1016/j.thromres.2004.03.014

10.1172/JCI6042

DepasseFBJ MnichJ LeFlemL GerotziafasGT SamamaMM.Effect of BAY 59‐7939—a novel oral direct factor Xa inhibitor—on clot‐bound factor Xa activity in vitro. Presented at: XXth Congress of the International Society on Thrombosis and Haemostasis;August 612 2005; Sydney Australia.

Calatzis A., 2000, The prothrombinase‐induced clotting test: a new technique for the monitoring of anticoagulants, Haemostasis, 30, 172

Calatzis A, 2006, Monitoring of direct FXa inhibitors using the prothrombinase‐induced clotting test (PiCT), Haemostaseologie, 26, 102

Graff JP‐WB, Monitoring effects of direct FXa‐inhibitors with a new one‐step prothrombinase‐induced clotting time (PiCT) assay: comparative in vitro investigation with heparin, enoxaparin, fondaparinux, and DX 9065a, Int J Clin Pharmacol.

10.1055/s-0037-1613868

10.1111/j.1538-7836.2004.00798.x

10.5414/CPP40135

10.1016/j.clpt.2005.06.011

10.1007/s00228-005-0043-5

10.1055/s-0038-1661594

10.1055/s-2006-939552

10.1080/00498250500250493

10.1111/j.1538-7836.2005.01657.x

10.1111/j.1538-7836.2005.01602.x

Eriksson BI, 2005, Prevention of venous thromboembolism after total hip replacement with once‐daily BAY 59‐7939—an oral, direct Xa inhibitor, Blood, 106, A280, 10.1182/blood.V106.11.280.280

10.1055/s-0038-1642666

10.1080/09537100400008059

10.1111/j.1365-2141.1999.01302.x

10.1097/00001721-200212000-00008

10.1161/01.ATV.0000077248.22632.88

10.1161/CIRCULATIONAHA.104.478222

Shimbo D, 2002, Antithrombotic effects of DX‐9065a, a direct factor Xa inhibitor: a comparative study in humans versus low molecular weight heparin, Thromb Haemost, 88, 733, 10.1055/s-0037-1613294

Paccaly A, 2005, Pharmacodynamic markers in the early clinical assessment of otamixaban, a direct factor Xa inhibitor, Thromb Haemost, 94, 1156, 10.1160/TH05-05-0347

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Thông tin xuất bản

Journal of Clinical Pharmacology

Tập 47 Số 11

1398-1407

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