Presented in part at the 48th Annual Meeting of the American Society of Hematology, 9–12 December, 2006, Orlando, Florida (abstract 917) and at the XXI International Society on Thrombosis and Haemostasis Congress, 6–12 July 2007, Geneva, Switzerland (abstract no. P-W-656).
Apixaban, an oral, direct and highly selective factor Xa inhibitor: in vitro, antithrombotic and antihemostatic studies
Version of Record online: 26 FEB 2008
© 2008 International Society on Thrombosis and Haemostasis
Journal of Thrombosis and Haemostasis
Volume 6, Issue 5, pages 820–829, May 2008
How to Cite
WONG, P. C., CRAIN, E. J., XIN, B., WEXLER, R. R., LAM, P. Y. S., PINTO, D. J., LUETTGEN, J. M. and KNABB, R. M. (2008), Apixaban, an oral, direct and highly selective factor Xa inhibitor: in vitro, antithrombotic and antihemostatic studies. Journal of Thrombosis and Haemostasis, 6: 820–829. doi: 10.1111/j.1538-7836.2008.02939.x
- Issue online: 26 FEB 2008
- Version of Record online: 26 FEB 2008
- Received 31 October 2007, accepted 15 February 2008
- blood coagulation;
- direct factor Xa inhibitor;
- oral anticoagulant;
Summary. Background: Apixaban is an oral, direct and highly selective factor Xa (FXa) inhibitor in late-stage clinical development for the prevention and treatment of thromboembolic diseases. Objective: We evaluated the in vitro properties of apixaban and its in vivo activities in rabbit models of thrombosis and hemostasis. Methods: Studies were conducted in arteriovenous-shunt thrombosis (AVST), venous thrombosis (VT), electrically mediated carotid arterial thrombosis (ECAT) and cuticle bleeding time (BT) models. Results: In vitro, apixaban is potent and selective, with a Ki of 0.08 nm for human FXa. It exhibited species difference in FXa inhibition [FXa Ki (nm): 0.16, rabbit; 1.3, rat; 1.7, dog] and anticoagulation [EC2× (μm, concentration required to double the prothrombin time): 3.6, human; 2.3, rabbit; 7.9, rat; 6.7, dog]. Apixaban at 10 μm did not alter human and rabbit platelet aggregation to ADP, γ-thrombin, and collagen. In vivo, the values for antithrombotic ED50 (dose that reduced thrombus weight or increased blood flow by 50% of the control) in AVST, VT and ECAT and the values for BT ED3× (dose that increased BT by 3-fold) were 0.27 ± 0.03, 0.11 ± 0.03, 0.07 ± 0.02 and > 3 mg kg−1 h−1 i.v. for apixaban, 0.05 ± 0.01, 0.05 ± 0.01, 0.27 ± 0.08 and > 3 mg kg−1 h−1 i.v. for the indirect FXa inhibitor fondaparinux, and 0.53 ± 0.04, 0.27 ± 0.01, 0.08 ± 0.01 and 0.70 ± 0.07 mg kg−1 day−1 p.o. for the oral anticoagulant warfarin, respectively. Conclusions: In summary, apixaban was effective in the prevention of experimental thrombosis at doses that preserve hemostasis in rabbits.