Antithrombotic effects of YM466, a synthesized direct inhibitor of factor Xa, in an arterio‐venous shunt thrombosis model in squirrel monkeys

The antithrombotic effects of YM466, a synthetic direct inhibitor of human factor Xa (FXa), were evaluated in an arterio‐venous shunt thrombosis model in squirrel monkeys. YM466 significantly inhibited thrombus formation after continuous IV zx infusion at doses of 3–30 µg/kg/h. Although prothrombin time (PT) was significantly prolonged at doses of 10 and 30 µg/kg/h, this effect was small (1.2‐ and 1.4‐fold of the control, respectively). Furthermore, YM466 had no effect on template bleeding time and activated partial thromboplastin time at any dose. Plasma anti‐FXa activity increased in a dose‐dependent manner correlating with the antithrombotic effect of YM466. Thrombin‐antithrombin III complex levels decreased to less than normal levels at 30 µg/kg/h of YM466. Mean plasma concentrations of YM466 measured by LC/MS/MS were 2.5, 10.5, 27.4, and 75.5 ng/ml at doses of 1, 3, 10, and 30 µg/kg/h, respectively. These results suggest that YM466 is a safe antithrombotic agent with low bleeding risk, and that plasma anti‐FXa activity may be a suitable parameter for monitoring its antithrombotic effect. Drug Dev. Res. 58:190–195, 2003.