Pharmacokinetics and pharmacodynamics of prasugrel, a thienopyridine P2Y12 inhibitor

Abstract

The platelet P2Y12 receptor has proved an effective target for therapeutic inhibition of arterial thrombosis, as demonstrated by the significant reductions in cardiovascular events in patients receiving the thienopyridine agents ticlopidine and clopidogrel. However, limitations of these drugs have led to the development of alternative antiplatelet agents including prasugrel (CS-747), an oral thienopyridine with a rapid onset of action, consistent antiplatelet activity, and prolonged duration of effect. Prasugrel is a prodrug that is metabolized to one active metabolite (R-138727) and numerous inactive metabolites. Absorption is complete and rapid, with mean time to peak plasma concentration of approximately 30 minutes for R-138727. The pharmacokinetics of prasugrel metabolites were linear and dose proportional in healthy volunteers. Median plasma half-life of the active metabolite is approximately 4 hours, and excretion is mainly urinary. Plasma clearance data suggest that prasugrel metabolism does not vary significantly among individuals. Pharmacodynamic studies have shown potent and selective P2Y12 blockade and dose-dependent inhibition of platelet aggregation with prasugrel (or R-138727). Onset of antiplatelet action is within 30 minutes, and steady state is reached in 3 days. Inhibition of platelet aggregation by prasugrel has been shown to be more rapid, more potent (on a mg/bodyweight basis), and more consistent than that with clopidogrel. Prasugrel does not appear to interact to any clinically relevant extent with other drugs, including those also metabolized by the hepatic cytochrome P450 isoenzymes CYP3A4, CYP2C9, CYP2C19, and CYP2B6, which are responsible for prasugrel metabolism. Thus, prasugrel has a pharmacokinetic and pharmacodynamic profile that compares favorably with those of existing antiplatelet agents.