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

Authors

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

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

References
1 Hirsh J, Raschke R. Heparin and low-molecularweight heparin: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 1885-203S.
2 Turpie AG, Gallus AS, Hoek JA. A synthetic pentasaccharide for the prevention of deep-vein thrombosis after total hip replacement. N Engl J Med 2001; 344: 619-625.
3 Bauer KA, Eriksson BI, Lassen MR. et al. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. N Engl J Med 2001; 345: 1305-1310.
4 Turpie AG, Bauer KA, Eriksson BI. et al. Postoperative fondaparinux versus postoperative enoxaparin for prevention of venous thromboembolism after elective hip-replacement surgery: a randomised double-blind trial. Lancet 2002; 359: 1721-1726.
5 Buller HR, Davidson BL, Decousus H. et al. Fondaparinux or enoxaparin for the initial treatment of symptomatic deep venous thrombosis: a randomized trial. Ann Intern Med 2004; 140: 867-873.
6 Ansell J, Hirsh J, Poller L. et al. The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 204S-233S.
7 McCormick D, Gurwitz JH, Goldberg RJ. et al. Prevalence and quality of warfarin use for patients with atrial fibrillation in the long-term care setting. Arch Intern Med 2001; 161: 2458-2463.
8 Ruivard M, Berger C, Achaibi A. et al. Physician compliance with outpatient oral anticoagulant guidelines in Auvergne, France. J Gen Intern Med 2003; 18: 903-907.
9 Scott PA, Pancioli AM, Davis LA. et al. Prevalence of atrial fibrillation and antithrombotic prophylaxis in emergency department patients. Stroke 2002; 33: 2664-2669.
10 Perzborn E, Strassburger J, Wilmen A. et al. In vitro and in vivo studies of the novel antithrombotic agent BAY 59–7939---an oral, direct Factor Xa inhibitor. J Thromb Haemost 2005; 3: 514-521.
11 Depasse F, Busson J, Mnich J. et al. Effect of BAY 59–7939 – a novel, oral, direct Factor Xa inhibitor – on clot-bound Factor Xa activity in vitro. J Thromb Haemost 2005; 3 Abstract P1104
12 Weinz C, Buetehorn U, Daehler HP. et al. Pharmacokinetics of BAY 59–7939 – an oral, direct Factor Xa inhibitor – in rats and dogs. Xenobiotica 2005; 35: 891-910.
13 Kubitza D, Becka M, Voith B. et al. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59–7939, an oral, direct factor Xa inhibitor. Clin Pharmacol Ther 2005; 78: 412-421.
14 Eriksson BI, Borris L, Dahl OE. et al. Oral, direct Factor Xa inhibition with BAY 59–7939 for the prevention of venous thromboembolism after total hip replacement. J Thromb Haemost 2006; 4: 121-128.
15 Turpie AG, Fisher WD, Bauer KA. et al. BAY 59–7939: an oral, direct Factor Xa inhibitor for the prevention of venous thromboembolism in patients after total knee replacement. A phase II dose-ranging study. J Thromb Haemost 2005; 3: 2479-2486.
16 Berry CN, Girard D, Girardot C. et al. Antithrombotic activity of argatroban in experimental thrombosis in the rabbit. Semin Thromb Hemost 1996; 22: 233-241.
17 Millet J, Theveniaux J, Brown NL. The venous antithrombotic profile of naroparcil in the rabbit. Thromb Haemost 1994; 72: 874-879.
18 Saivin S, Caranobe C, Petitou M. et al. Antithrombotic activity, bleeding effect and pharmacodynamics of a succinyl derivative of dermatan sulphate in rabbits. Br J Haematol 1992; 80: 509-513.
19 Biemond BJ, Levi M, Nurmohamed MT. et al. Additive effect of the combined administration of low molecular weight heparin and recombinant hirudin on thrombus growth in a rabbit jugular vein thrombosis model. Thromb Haemost 1994; 72: 377-380.
20 Biemond BJ, Friederich PW, Levi M. et al. Comparison of sustained antithrombotic effects of inhibitors of thrombin and factor Xa in experimental thrombosis. Circulation 1996; 93: 153-160.
21 Friederich PW, Keller TT, Biemond BJ. et al. Successful attenuation of venous thrombus growth in rabbits after the administration of a novel oral thrombin inhibitor. Thromb Haemost 2000; 84: 858-864.
22 Levi M, Friederich PW, Middleton S. et al. Fibrinogen- coated albumin microcapsules reduce bleeding in severely thrombocytopenic rabbits. Nat Med 1999; 5: 107-111.
23 ten Cate H, Lamping RJ, Henny CP. et al. Automated amidolytic method for determining heparin, a heparinoid, and a low-Mr heparin fragment, based on their anti-Xa activity. Clin Chem 1984; 30: 860-864.
24 Weinz C, Schwartz T, Pleiss U. et al. Metabolism and distribution of [14C]BAY 59–7939 – an oral, direct factor Xa inhibitor – in rat, dog and human. Drug Metab Rev 2004; 36 (Suppl. 01) (Suppl) 98 (Abstract 196)
25 Buller HR, Davidson BL, Decousus H. et al. Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. N Engl J Med 2003; 349: 1695-1702.
26 Leadley Jr RJ. Coagulation factor Xa inhibition: biological background and rationale. Curr Top Med Chem 2001; 1: 151-159.
27 Wong PC, Crain EJ, Watson CA. et al. Nonpeptide factor Xa inhibitors III: effects of DPC423, an orallyactive pyrazole antithrombotic agent, on arterial thrombosis in rabbits. J Pharmacol Exp Ther 2002; 303: 993-1000.