Preclinical and Clinical Characteristics of Rivaroxaban: A Novel, Oral, Direct Factor Xa Inhibitor

ABSTRACT

There are several novel anticoagulants in development that target factor Xa(FXa)-the pivotal point of the coagulation cascade. One promising agent is rivaroxaban (a highly selective, oral, direct FXa inhibitor), which is in advanced clinical development for the prevention and treatment of thromboembolic disorders. Oral rivaroxaban may be given in fixed once-daily doses, with the potential for no coagulation monitoring. These properties, along with results from preclinical and clinical studies, suggest that rivaroxaban may have advantages over current treatments. Studies in arterial and venous animal models demonstrated that rivaroxaban has potent antithrombotic effects, without prolonging bleeding times. In healthy subjects, rivaroxaban was well tolerated, with a predictable pharmacological profile and a low propensity for clinically relevant drug-drug interactions. Phase II studies of rivaroxaban for the prevention of venous thromboembolism (VTE) after major orthopedic surgery support these findings. The results also suggested that a total daily dose range of 5 to 20 mg rivaroxaban had similar efficacy and safety to enoxaparin, and that 10 mg rivaroxaban once daily was the optimal dose. This review assesses the preclinical and clinical characteristics of rivaroxaban, and discusses phase II findings with rivaroxaban for the prevention of VTE after major orthopedic surgery.

Rivaroxaban - BAY 59-7939 - factor Xa(FXa) inhibitor - oral anticoagulants - venous thromboembolism

REFERENCES

• 1 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
• 2 Roehrig S, Straub A, Pohlmann J et al.. Discovery of the novel antithrombotic agent 5-chloro-N-({(5S)-2-oxo-3- [4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene- 2-carboxamide (BAY 59-7939): an oral, direct factor Xa inhibitor.  J Med Chem. 2005;  48 5900-5908
• 3 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 P1104 , (abst)
• 4 Gerotziafas G T, Elalamy I, Chakroun T et al.. The oral, direct factor Xa inhibitor BAY 59-7939 inhibits thrombin generation in vitro after tissue factor pathway activation.  J Thromb Haemost. 2007;  5 886-888
• 5 Biemond B J, Friederich P W, Levi M et al.. Successful inhibition of venous thrombus growth after oral administration of BAY 59-7939, a direct factor Xa inhibitor in rabbits.  Pathophysiol Haemost Thromb. 2004;  33 24 , (abst OC014)
• 6 Perzborn E, Arndt B, Fischer E et al.. Antithrombotic effects of rivaroxaban-an oral, direct factor Xa inhibitor-in animal models of arterial and venous thrombosis: comparison with enoxaparin, an antithrombin-dependent anticoagulant.  Eur Heart J. 2006;  27(suppl) 762 , (abst)
• 7 Perzborn E, Arndt B, Harwardt M et al.. Antithrombotic efficacy of BAY 59-7939-an oral, direct factor Xa inhibitor-compared with fondaparinux in animal arterial thrombosis and thromboembolic death models.  Eur Heart J. 2005;  26(suppl) 481 , (abst)
• 8 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
• 9 Kubitza D, Becka M, Wensing G et al.. Safety, pharmacodynamics, and pharmacokinetics of BAY 59-7939-an oral, direct factor Xa inhibitor-after multiple dosing in healthy male subjects.  Eur J Clin Pharmacol. 2005;  61 873-880
• 10 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 1) 98 , (abst 196)
• 11 Harder S, Graff J, Hentig N V et al.. Effects of BAY 59-7939, an oral, direct factor Xa inhibitor, on thrombin generation in healthy volunteers.  Blood. 2003;  102 3003 , (abst)
• 12 Perzborn E, Strassburger J, Wilmen A et al.. Biochemical and pharmacologic properties of BAY 59-7939, an oral, direct factor Xa inhibitor.  Pathophysiol Haemost Thromb. 2004;  33(suppl 2) PO079 , (abst)
• 13 Fareed J, Hoppensteadt D, Maddenini J et al.. Antithrombotic mechanism of action of BAY 59-7939-a novel, oral, direct factor Xa inhibitor. Poster presented at Intl Soc Thromb Haemost XXth Congress, Sydney, Australia August 6-12, 2005
• 14 Kubitza D, Becka M, Mueck W, Zuehlsdorf M. Safety, tolerability, pharmacodynamics, and pharmacokinetics of rivaroxaban-an oral, direct factor Xa inhibitor-are not affected by aspirin.  J Clin Pharmacol. 2006;  46 981-990
• 15 Kubitza D, Becka M, Mueck W, Zuehlsdorf M. Rivaroxaban (BAY 59-7939)-an oral, direct factor Xa inhibitor-has no clinically relevant interaction with naproxen.  Br J Clin Pharmacol. 2007;  63(4) 469-476
• 16 Kubitza D, Mueck W, Becka M. The oral, direct factor Xa inhibitor BAY 59-7939 does not prolong the QTc interval.  J Clin Pharmacol. 2006;  46 703 , (abst 12)
• 17 Kubitza D, Becka M, Zuehlsdorf M, Mueck W. No interaction between the novel, oral direct factor Xa inhibitor BAY 59-7939 and digoxin.  J Clin Pharmacol. 2006;  46 702 , (abst 11)
• 18 Kubitza D, Becka M, Voith B, Zuehlsdorf M. Effect of enoxaparin on the safety, tolerability, pharmacodynamics and pharmacokinetics of BAY 59-7939-an oral, direct factor Xa inhibitor.  J Thromb Haemost. 2005;  3(suppl 1) 1704
• 19 Geerts W H, Pineo G F, Heit J A et al.. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.  Chest. 2004;  126 338S-400S
• 20 Ansell J, Bergqvist D. Current options in the prevention of thromboembolic disease.  Drugs. 2004;  64 1-5
• 21 Dahl O E. Orthopaedic surgery as a model for drug development in thrombosis.  Drugs. 2004;  64(suppl 1) 17-25
• 22 Eriksson B I, Borris L C, Dahl O E et al.. Dose-escalation study of rivaroxaban (BAY 59-7939)-an oral, direct factor XA inhibitor-for the prevention of venous thromboembolism in patients undergoing total hip replacement.  Thromb Res. 2007; Feb 9(Epub ahead of print); 
• 23 Eriksson B I, Borris L, Dahl O E 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
• 24 Turpie A G, Fisher W D, Bauer K A 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
• 25 Fisher W D, Eriksson B I, Bauer K A et al.. Rivaroxaban for thromboprophlylaxis after orthopaedic surgery: pooled analysis of two studies.  Thromb Haemost. 2007;  97(6) 931-937
• 26 Collignon F, Frydman A, Caplain H et al.. Comparison of the pharmacokinetic profiles of three low molecular mass heparins-dalteparin, enoxaparin and nadroparin-administered subcutaneously in healthy volunteers (doses for prevention of thromboembolism).  Thromb Haemost. 1995;  73 630-640
• 27 Eriksson B I, Borris L C, Dahl O E et al.. A once-daily, oral, direct factor Xa inhibitor, rivaroxaban (BAY 59-7939), for thromboprophylaxis after total hip replacement.  Circulation. 2006;  114 2374-2381
• 28 Mueck W, Eriksson B, Borris L et al.. Rivaroxaban for thromboprophylaxis in patients undergoing total hip replacement: comparison of pharmacokinetics and pharmacodynamics with once- and twice-daily dosing.  Blood. 2006;  108 P903(abst)
• 29 Kubitza D, Becka M, Mueck W, Zuehlsdorf M. The effect of extreme age, and gender, on the pharmacology and tolerability of rivaroxaban-an oral, direct factor Xa inhibitor.  Blood. 2006;  108 P905(abst)
• 30 Halabi A, Maatouk H, Klause N et al.. Effect of renal impairment on the pharmacology of rivaroxaban (BAY 59-7939)-an oral, direct factor Xa inhibitor.  Blood. 2006;  108 P913(abst)
• 31 Kubitza D, Becka M, Zuehlsdorf M, Mueck W. Body weight has limited influence on the safety, tolerability, pharmacokinetics, or pharmacodynamics of rivaroxaban (BAY 59-7939) in healthy subjects.  J Clin Pharmacol. 2007;  47 218-226