Biochemical and Pharmacological Profiles of YM150, an Oral Direct Factor Xa Inhibitor. (2006)

Abstract YM150 is an oral direct FXa inhibitor used as prophylaxis for venous thromboembolism in patients undergoing elective primary hip replacement surgery (Blood106: 530a (abstract#1865), 2005). No preclinical data has been reported for this compound so far. The biochemical and pharmacological properties of YM150 were evaluated in this study. In addition, the anticoagulation activity of orally administered YM150 was compared with that of YM466, a 1st generation FXa inhibitor, in fed cynomolgus monkeys and in bile duct-cannulated rats. The Ki values for YM150 and YM-222714, its major metabolite, against human FXa were 0.031 and 0.020 μM, respectively (n=4). Those for other serine proteases, such as trypsin, plasmin, and thrombin, were greater than 10 μM. YM150 and YM-222714 doubled the FXa clotting time and PT at 2.0 and 1.8 μM, and 1.2 and 0.95 μM, respectively (n=4). They also strongly inhibited prothrombin activation induced by free Xa, prothrombinase, and whole-blood clots with similar IC50 values (0.025–0.082 μM, n=5). In contrast, enoxaparin was much less effective at inhibiting prothrombin activation induced by prothrombinase or clots than prothrombin activation induced by free Xa (IC50 values: 330, 120, and 3.5 mU/mL, respectively, n=5). In the thromboplastin-induced venous thrombosis model in rats, YM150 (0.3–10 mg/kg i.d.) exerted its antithrombotic effects dose-dependently, with significance at 1 mg/kg (ED50: 0.97 mg/kg, n=6). YM150 prolonged the PT slightly at 10 and 30 mg/kg (1.2 and 1.4 times that of the control group), but the template bleeding time was not affected at 30 mg/kg. Although warfarin also exerted antithrombotic effects dose-dependently and with significance at 0.2 mg/kg (ED50: 0.12 mg/kg, n=6), this dose level markedly prolonged PT and bleeding time (4.4 and 2.2 times that of the control group). In an arterio-venous shunt thrombosis model in rabbits, YM150 (1–10 mg/kg p.o.) exerted antithrombotic effects dose-dependently and with significance at 10 mg/kg (ED50: 4.8 mg/kg, n=6), but did not prolong bleeding time at any dose level. Warfarin also exerted antithrombotic effects dose-dependently and with significance at 0.1 mg/kg/day (ED50: 0.29 mg/kg, n=6). Bleeding time was prolonged significantly at this dose level (control: 3.5 min warfarin: 5.8 min). The plasma concentrations of YM-222714 were 129+/−73.7, 396+/−224, and 3,641+/−902 ng/mL after dosing 1, 3, and 10 mg/kg, respectively, while those of YM150 was substantially lower (less than 125+/−265 ng/mL at 10 mg/kg). In fasted cynomolgus monkeys, oral administration of either YM150 (3–30 mg/kg) or YM466 (1–10 mg/kg) dose-dependently prolonged PT. The anticoagulation activity of YM466 was 3 times that of YM150, but this activity decreased significantly in the presence of food, while that of YM150 did not. The peak plasma anti-FXa activity after oral administration of 3 mg/kg YM150 to bile duct-cannulated rats and sham-operated rats were 67.7% and 68.5%, respectively. In contrast, those of 3 mg/kg YM466 were 57.4% and 26.2%, respectively. These data suggest that food or bile interferes with YM150 less than it does with YM466. In conclusion, YM150 is a promising oral FXa inhibitor that carries a bleeding risk that is less than that of warfarin. It also seems be well-absorbed without interference by food or bile. The in vivo antithrombotic activity of YM150 after oral administration was also determined to be produced by its active metabolite, YM-222714.