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Apixaban, an oral, direct and highly selective factor Xa inhibitor: in vitro , antithrombotic and antihemostatic studies
Author(s) -
WONG P. C.,
CRAIN E. J.,
XIN B.,
WEXLER R. R.,
LAM P. Y. S.,
PINTO D. J.,
LUETTGEN J. M.,
KNABB R. M.
Publication year - 2008
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/j.1538-7836.2008.02939.x
Subject(s) - apixaban , antithrombotic , pharmacology , hemostasis , medicine , bleeding time , thrombus , in vivo , thrombosis , rivaroxaban , chemistry , platelet , warfarin , biology , atrial fibrillation , platelet aggregation , microbiology and biotechnology
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 K i of 0.08 n m for human FXa. It exhibited species difference in FXa inhibition [FXa K i (n m ): 0.16, rabbit; 1.3, rat; 1.7, dog] and anticoagulation [EC 2× (μ m , concentration required to double the prothrombin time): 3.6, human; 2.3, rabbit; 7.9, rat; 6.7, dog]. Apixaban at 10 μ m did not alter human and rabbit platelet aggregation to ADP, γ‐thrombin, and collagen. In vivo , the values for antithrombotic ED 50 (dose that reduced thrombus weight or increased blood flow by 50% of the control) in AVST, VT and ECAT and the values for BT ED 3× (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.