Effects of the Proton Pump Inhibitor Lansoprazole on the Pharmacokinetics and Pharmacodynamics of Prasugrel and Clopidogrel

TLDR

Prasugrel and clopidogrel are thienopyridine prodrugs that are metabolized to active inhibitors of the platelet P2Y12 ADP receptor. In a 4‑period crossover study, healthy volunteers received single doses of prasugrel 60 mg or clopidogrel 300 mg with or without lansoprazole 30 mg qd, and the study measured plasma Cmax and AUC of prasugrel’s active metabolite R‑138727 and clopidogrel’s inactive metabolite SR26334, as well as platelet aggregation inhibition 4–24 h post‑dose. Lansoprazole reduced R‑138727 exposure by 13 % and Cmax by 29 % but did not alter prasugrel‑induced platelet inhibition, whereas it tended to lower clopidogrel‑induced inhibition, especially in subjects with high baseline IPA, leading the authors to conclude that a prasugrel dose adjustment is unlikely needed when combined with a proton‑pump inhibitor.

Abstract

Prasugrel and clopidogrel, thienopyridine prodrugs, are each metabolized to an active metabolite that inhibits the platelet P2Y(12) ADP receptor. In this open-label, 4-period crossover study, the effects of the proton pump inhibitor lansoprazole on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel were assessed in healthy subjects given single doses of prasugrel 60 mg and clopidogrel 300 mg with and without concurrent lansoprazole 30 mg qd. C(max) and AUC(0-tlast) of prasugrel's active metabolite, R-138727, and clopidogrel's inactive carboxylic acid metabolite, SR26334, were assessed. Inhibition of platelet aggregation (IPA) was measured by turbidimetric aggregometry 4 to 24 hours after each treatment. Lansoprazole (1) decreased R-138727 AUC(0-tlast) and C(max) by 13% and 29%, respectively, but did not affect IPA after the prasugrel dose, and (2) did not affect SR62334 exposure but tended to lower IPA after a clopidogrel dose. A retrospective tertile analysis showed in subjects with high IPA after a clopidogrel dose alone that lansoprazole decreased IPA, whereas IPA was unaffected in these same subjects after a prasugrel dose. The overall data suggest that a prasugrel dose adjustment is not likely warranted in an individual taking prasugrel with a proton pump inhibitor such as lansoprazole.