Pre-clinical pharmacodynamic study of a novel oral factor Xa inhibitor zifaxaban

Zifaxaban is an orally active, direct Factor Xa (FXa) inhibitor that is in development for the prevention and treatment of arterial and venous thrombosis. This study was conducted to investigate the biochemical and pharmacological activity of zifaxaban. In vitro activity was evaluated by enzyme, platelet aggregation, and clotting assays. In vivo effects were examined in venous thrombosis, arteriovenous-shunt thrombosis, carotid thrombosis, and bleeding models in rats. Zifaxaban competitively inhibits human FXa (IC₅₀ = 11.1 nM) with > 10,000-fold greater selectivity than other serine proteases. It did not impair platelet aggregation induced by collagen, adenosine diphosphate (ADP) or arachidonic acid. It significantly prolonged clotting time, prothrombin time (PT), and activated partial thromboplastin time (APTT) in the plasma of humans, rabbits, and rats, with a relatively weak effect on thrombin time (TT). In venous thrombosis models in rats, zifaxaban strongly suppressed thrombus formation with ED₅₀ values of 3.09 mg/kg, and its best efficacy time occurred at 2 h after administration. In arteriovenous-shunt thrombosis and carotid thrombosis models in rats, it inhibited thrombus formation in a dose-dependent manner. And in the rat tail bleeding assay, it showed a trend of less bleeding than rivaroxaban at doses that achieved the same antithrombotic effect. In conclusion, zifaxaban is a selective and direct FXa inhibitor and a promising oral anticoagulant for the prophylaxis and treatment of thromboembolic diseases.