Platelet inhibitory activity and pharmacokinetics of prasugrel (CS-747) a novel thienopyridine P2Y12 inhibitor: A multiple-dose study in healthy humans

Abstract

This double-blind, placebo-controlled trial evaluated the safety, pharmacodynamics, and pharmacokinetics of prasugrel (CS-747, LY640315), a novel thienopyridine P2Y₁₂ ADP receptor antagonist, during multiple oral dosing in healthy subjects. Eighteen subjects received placebo, or prasugrel 2.5 or 10 mg, orally, daily for 10 days. Adverse events were recorded and blood samples for measurement of platelet aggregation, bleeding time, and prasugrel metabolite concentrations were obtained. Two bleeding events were experienced in the prasugrel 10 mg dose group and one in the placebo group. Neither of the events was considered serious. ADP-induced platelet aggregation accumulated over the 10-day study period, reaching a steady state by days 2–4 following administration of prasugrel 10 mg daily. Limited inhibition of platelet aggregation was obtained with prasugrel 2.5 mg. In the 10-mg dose group at day 5, 4 h postdose, with 20 µM ADP as the agonist, inhibition of platelet aggregation was 61.2 ± 5.6 vs. 17.9 ± 6.2% in the placebo group (P < 0.01). Recovery of platelet aggregation was observed 48 h after the last dose of prasugrel 10 mg, but was only partial, consistent with irreversible platelet inhibition. The mean bleeding time was prolonged by day 5 at 4 h postdose in all subjects in the prasugrel 10 mg dose group (prasugrel 10 mg, 1058 ± 412 s vs. placebo, 196 ± 74 s; P < 0.001). The maximum plasma concentration of metabolites increased with prasugrel dose and there was no accumulation of metabolites over the 10-day study period. This study indicated that prasugrel 10 mg daily for 10 days was well tolerated and at steady-state provided sustained high levels of inhibition of platelet aggregation.