Favorable therapeutic index of the direct factor Xa inhibitors, apixaban and rivaroxaban, compared with the thrombin inhibitor dabigatran in rabbits

Abstract

To cite this article: Wong PC, Crain EJ, Watson CA, Xin B. Favorable therapeutic index of the direct factor Xa inhibitors, apixaban and rivaroxaban, compared with the thrombin inhibitor dabigatran in rabbits. J Thromb Haemost 2009; 7: 1313-20.Summary. Background: Apixaban is an oral, direct factor Xa (FXa) inhibitor in late-stage clinical development. This study assessed effects of the direct FXa inhibitors, apixaban and rivaroxaban, vs. the direct thrombin inhibitor, dabigatran, on venous thrombosis (VT), bleeding time (BT) and clotting times in rabbits. Methods: We induced the formation of non-occlusive thrombus in VT models by placing threads in the vena cava, and induced bleeding by the incision of cuticles in anesthetized rabbits. Apixaban, rivaroxaban and dabigatran were infused IV to achieve a stable plasma level. Clotting times, including the activated partial thromboplastin time (aPTT), prothrombin time (PT), modified PT (mPT) and thrombin time (TT), were measured. Results: Apixaban, rivaroxaban and dabigatran exhibited dose-related efficacy in preventing VT with EC 50 of 65, 33 and 194 nM, respectively. At doses for 80% reduction of control thrombus, apixaban, rivaroxaban and dabigatran prolonged BT by 1.13 ± 0.02-, 1.9 ± 0.1-* and 4.4 ± 0.4-fold*, respectively (*P < 0.05, vs. apixaban). In the treatment model, these inhibitors equally prevented growth of a preformed thrombus. Antithrombotic doses of apixaban and rivaroxaban prolonged aPTT and PT by <3-fold with no effect on TT. Dabigatran was ‡50-fold more potent in prolonging TT than aPTT and PT. Of the clotting assays studied, apixaban, rivaroxaban and dabigatran responded the best to mPT. Conclusion: Comparable antithrombotic efficacy was observed between apixaban, rivaroxaban and dabigatran in the prevention and treatment of VT in rabbits. Apixaban and rivaroxaban exhibited lower BT compared with dabigatran at equivalent antithrombotic doses. The clinical significance of these findings remains to be determined.

A small-molecule factor XIa inhibitor produces antithrombotic efficacy with minimal bleeding time prolongation in rabbits

“…To provide additional confidence in the antithrombotic efficacy of small-molecule FXIa inhibitors, and to confirm FXIa as an attractive therapeutic target, it is critical to conduct full dose-response studies in multiple species under relevant experimental conditions. Rabbit models of thrombosis and hemostasis have been used extensively for the evaluation of antiplatelet agents and anticoagulants with good clinical correlates [24][25][26][27][28][29]. Therefore, we determined the in vitro and in vivo dose-response profiles of BMS-262084 in rabbits.…”

Metabolism, pharmacokinetics and pharmacodynamics of the factor Xa inhibitor apixaban in rabbits

“…It exhibits desirable and predictable pharmacokinetic (PK) and concentration-dependent pharmacodynamic (PD) responses in humans [9,10]. Apixaban has also demonstrated antithrombotic activity in preclinical animal models [8,11,12] and promising safety and efficacy results in clinical studies [13][14][15][16][17].…”

“…As rabbits are commonly used in the development of thrombosis disease models [8,11,12], we chose to study the metabolism, PK and PD of apixaban, following both oral and intravenous (IV) administration, in this animal model.…”

Oral Antithrombotic Effects of Acylhydrazone Derivatives

“…Arterial thrombus formation was also dose-dependently inhibited by rivaroxaban in rats (ED50 5.0 mg/kg) 32) . It is important to note that the antithrombotic effective dose of dabigatran and rivaroxaban did not markedly prolong bleeding times in rats or rabbits 32,33) . Although there are a wide variety of antithrombotics for the prophylaxis and treatment of thrombotic events, they all have significant adverse effects.…”