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

From Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (Dr Small, Dr Farid, Dr Weerakkody, Ms Li, Dr Brandt, Dr Winters); Lilly Research Centre, Ltd, Eli Lilly and Company, Windlesham, UK (Mr Payne); and Daiichi Sankyo, Inc, Parsippany, New Jersey (Dr Salazar).

Prasugrel and clopidogrel, thienopyridine prodrugs, are each metabolized to an active metabolite that inhibits the platelet P2Y₁₂ 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.

Key Words: Clopidogrel • prasugrel • lansoprazole • drug interaction

Address for correspondence: David S. Small, PhD, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center DC 0724, Indianapolis, IN 46285; e-mail: dsmall{at}lilly.com.

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