Abstract

Apixaban is a small-molecule, potent, reversible and direct inhibitor of human coagulation factor Xa (FXa) (Ki = 0.08 nM) with greater than 30000-fold selectivity over other coagulation proteases. It is orally bioavailable in rats, dogs, chimpanzees and humans, and is currently in clinical development for prevention and treatment of thromboembolic diseases. The objective of this study was to compare antithrombotic and bleeding time effects of apixaban and warfarin in rabbits. We selected rabbits as the animal model because apixaban has similar potency in inhibiting human and rabbit FXa, but is less potent in inhibiting rat and dog FXa (Ki (nM): 0.16, rabbit; 1.3, rat; 1.8, dog). We induced the formation of venous thrombus by placing threads in the vena cava, and bleeding by the incision of cuticles in anesthetized rabbits. Apixaban was infused IV 60 min before the initiation of thrombosis. Warfarin was administered orally for 4 days before the study. Thrombus weight averaged 73±5 mg and bleeding time averaged 183±7 s in the vehicle group (n=6 per group). Apixaban and warfarin inhibited the formation of venous thrombus in a dose-dependent manner. The estimated IC50 for apixaban was 0.16±0.04 μM. At antithrombotic doses studied, apixaban did not alter blood pressure and heart rate, suggesting hemodynamic effects are not likely to be involved in its antithrombotic activity. At the antithrombotic ID80, apixaban and warfarin increased bleeding time by 9±4% and 516±24%, respectively (n=6 per group). At this dose, apixaban increased ex vivo activated partial thromboplastin time and prothrombin time to 1.4±0.1 and 1.7±0.1 times control, respectively, and warfarin increased prothrombin time to 4.5±0.1 times control. Apixaban at antithrombotic doses selectively inhibited ex vivo FXa but not thrombin activity. In summary, these findings demonstrate potent activity of apixaban as a selective FXa inhibitor exhibiting potential strong efficacy in prevention of venous thrombosis at doses that preserve hemostasis and produce less increases in systemic anticoagulation than warfarin.

Disclosures: Bristol-Myers Squibb Company.; Bristol-Myers Squibb Company.

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