Antiplatelet and antithrombotic activity of multiple oral dosing of
prasugrel were evaluated in several animal species.
Prasugrel's active metabolite concentration-relatedly inhibited in vitro
ADP-induced aggregation of rat, rabbit, dog, monkey and human platelets.
Oral administration of
prasugrel to dogs (0.03-0.3 mg/kg/day) and monkeys (0.1 and 0.3 mg/kg/day) once a day for 14 days resulted in potent, dose-related and cumulative inhibition of
ADP-induced platelet aggregation. The inhibitory effects reached a plateau on days 3 to 5 and thereafter were maintained during dosing. Inhibition decreased gradually after cessation of dosing with near full recovery by 7 days after last dose. Antiplatelet and antithrombotic activity of
prasugrel and
clopidogrel were further examined in rats. Multiple oral dosing of
prasugrel (0.3-3 mg/kg/day) to rats resulted in more potent inhibition of platelet aggregation compared to
clopidogrel (3-30 mg/kg/day) and
ticlopidine (30-300 mg/kg/day). Separate experiments confirmed that platelet inhibition was associated with inhibition of [(3)H]-2-
methylthio-ADP binding to rat platelets. In a rat model of electrically-induced arterial
thrombosis,
prasugrel (0.1-1 mg/kg/day, p.o.) significantly prolonged the time to
arterial occlusion and increased the duration of arterial patency. The inhibition of platelet aggregation of
prasugrel was about 10 and 300 times more potent than
clopidogrel and
ticlopidine, respectively. Overall these results show that in several species multiple
oral administration of
prasugrel results in more potent inhibition of platelet aggregation and
thrombus formation than
clopidogrel and
ticlopidine, and that these effects are mediated by inhibition of platelet
ADP receptors.