Prasugrel

Jakubowski, Joseph A. Lilly Corporate Center, Mail Drop Code 1854, Indianapolis, IN 46285, United States.

Activation of platelet P2Y12 ADP receptors at sites of atherosclerotic plaque rupture promotes platelet activation, aggregation and occlusive thrombus formation. P2Y12 is the target of the thienopyridine class of oral antiplatelet agents that includes ticlopidine and clopidogrel. Despite providing important clinical benefit, clopidogrel’s platelet inhibitory profile has several limitations; namely its onset of action is relatively slow and the extent and consistency of inhibition are highly variable. Prasugrel is a 3rd generation thienopyridyl P2Y12 antagonist which, like clopidogrel, is a prodrug requiring metabolism in vivo to an active metabolite (R-138727). Prasugrel’s distinct chemical structure allows for rapid and efficient conversion to this active metabolite which has been shown to inhibit a wide range of ADP-mediated platelet activities. Clinical data have shown greater platelet inhibition and consistency of inhibition with prasugrel compared to clopidogrel. Pharmacokinetic studies have shown that the amount of each active metabolite generated in vivo is quite different, with prasugrel generating substantially more of its active metabolite compared with clopidogrel despite being used at a lower dose. Genetic studies have demonstrated that variations in the gene encoding CYP-450 2C19 do not affect the activity of prasugrel but result in reduced exposure to clopidogrel’s active metabolite and diminished platelet inhibition. Taken together, these data provide a mechanistic basis for the distinct profile of greater and more consistent platelet inhibition observed with prasugrel. The recently completed phase 3 trial (TRITON TIMI-38) demonstrated that compared to clopidogrel, prasugrel resulted in a 19% relative reduction in the risk of ischemic events in patients with acute coronary syndrome undergoing percutaneous coronary intervention. Notably there was a 52% relative reduction in the risk of stent thrombosis in the prasugrel treated patients compared to those on clopidogrel. In the overall TRITON population, prasugrel was associated with 32% increase in the relative risk of major bleeding compared to patients treated with clopidogrel.