Prevention and treatment of experimental thrombosis in rabbits with rivaroxaban (BAY 597939) – an oral, direct factor Xa inhibitor

Bart J. Biemond; Elisabeth Perzborn; Philip W. Friederich; Marcel Levi; Ulf Buetehorn; Harry R. Büller

doi:10.1160/TH06-11-0620

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2007; 97(03): 471-477
DOI: 10.1160/TH06-11-0620

Animal Models

Schattauer GmbH

Prevention and treatment of experimental thrombosis in rabbits with rivaroxaban (BAY 597939) – an oral, direct factor Xa inhibitor

Bart J. Biemond

¹Department of Haematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

,

Elisabeth Perzborn

²Cardiovascular Pharmacology, Pharma R&D Discovery Research, Bayer HealthCare AG, Wuppertal, Germany

,

Philip W. Friederich

³Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

,

Marcel Levi

³Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

,

Ulf Buetehorn

⁴Preclinical Pharmacokinetics, Bayer HealthCare AG, Wuppertal, Germany

,

Harry R. Büller

³Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

› Author Affiliations

Abstract

Summary

Current anticoagulant therapies for the prevention and treatment of thromboembolic disorders have many drawbacks: vitamin K antagonists interact with food and drugs and require frequent laboratory monitoring, and heparins require parenteral administration. Oral rivaroxaban (BAY 597939) is a new, highly selective and potent direct factor-Xa (FXa) inhibitor with a predictable pharmacodynamic and pharmacokinetic profile and could therefore be an attractive antithrombotic drug. It was the objective of this study to investigate the antithrombotic efficacy of oral rivaroxaban in two rabbit models of experimental venous thrombosis. In the venous stasis (prevention) model, animals were randomized to receive oral rivaroxaban 0.3, 1.0, 3.0 or 10.0 mg/kg or vehicle control. Thrombosis was induced by jugular vein stasis and injection of thromboplastin into the ear vein. In the venous thrombosis (treatment) model, intravenous (1.0 and 3.0 mg/kg) and oral (3.0 mg/kg) rivaroxaban was compared with intravenous nadroparin (40 U bolus and 20 U/h), fon-daparinux (42 Mg/kg) and vehicle control. Thrombus growth was assessed by measuring the accretion of radiolabeled fibrinogen into preformed clots in the jugular veins. Bleeding was assessed using an ear bleeding model. In the prevention model, rivaroxaban reduced thrombus formation dose-dependently (calculated ED₅₀ 1.3 mg/kg). In the treatment model, oral rivaroxaban (3.0 mg/kg) reduced thrombus growth to a similar extent to intravenous rivaroxaban (1.0 mg/kg), nadroparin and fondapari-nux. Oral rivaroxaban did not prolong bleeding time. In conclusion, the orally available selective, direct FXa inhibitor rivaroxaban is effective in the prevention and treatment of venous thrombosis in two well-established models of experimental thrombosis.

Keywords

Factor Xa inhibitor - venous thrombosis - prophylaxis - rivar-oxaban - oral anticoagulant

Full Text

References

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