Effects of rabeprazole on the antiplatelet effects and pharmacokinetics of clopidogrel in healthy volunteers.: PK/PD interaction between rabeprazole and clopidogrel

Abstract : BACKGROUND: Several studies have suggested that proton-pump inhibitors (PPIs), mostly omeprazole, interact with clopidogrel efficacy by inhibiting the formation of its active metabolite via CYP2C19 inhibition. Whether this occurs with all PPIs is a matter of debate. As rabeprazole is a less potent CYP2C19 inhibitor than other PPIs, we studied the interaction between rabeprazole and the antiplatelet actions and pharmacokinetics of clopidogrel. AIM: To demonstrate the non-inferiority of rabeprazole over placebo using change in platelet reactivity index (PRI; vasodilator-stimulated phosphoprotein [VASP] assay) in a predefined population of good clopidogrel responders. Omeprazole was used as the positive control. METHODS: In this randomized three-period crossover study in healthy volunteers, 36 healthy men received clopidogrel (75mg/day for 7 days) with placebo, omeprazole (20mg/day) or rabeprazole (20mg/day). Clopidogrel antiplatelet effects and disposition kinetics were assessed on day 7 of combination therapy. Non-inferiority threshold was predefined as an upper limit of the 90% confidence interval for the difference in change in PRI between placebo and rabeprazole of<10% in good clopidogrel responders. RESULTS: In good clopidogrel responders (inhibition of VASP index>30%), the clopidogrel antiplatelet effect remained non-inferior to placebo during rabeprazole (difference 3.4% [-1.7; 8.5]) but not omeprazole (difference 7.5% [2.5; 12.6]) co-administration. The AUC0-24 and Cmax of active clopidogrel metabolite decreased with both omeprazole and rabeprazole, and conditions of bioequivalence were not met, except for AUC0-24 with rabeprazole. CONCLUSIONS: Rabeprazole does not interact with clopidogrel to the same extent as omeprazole. However, under our experimental conditions and proton-pump inhibitor doses, there was no significant pharmacodynamic interaction between rabeprazole or omeprazole and clopidogrel, despite a significant decrease in the formation of clopidogrel active metabolite.
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Archives of cardiovascular diseases, Elsevier/French Society of Cardiology, 2013, 106 (12), pp.661-671. 〈10.1016/j.acvd.2013.09.002〉
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Contributeur : Christian Funck-Brentano <>
Soumis le : jeudi 28 novembre 2013 - 16:09:54
Dernière modification le : jeudi 11 janvier 2018 - 06:20:15
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Christian Funck-Brentano, Jean Szymezak, Olivier Steichen, Dominique Ducint, Mathieu Molimard, et al.. Effects of rabeprazole on the antiplatelet effects and pharmacokinetics of clopidogrel in healthy volunteers.: PK/PD interaction between rabeprazole and clopidogrel. Archives of cardiovascular diseases, Elsevier/French Society of Cardiology, 2013, 106 (12), pp.661-671. 〈10.1016/j.acvd.2013.09.002〉. 〈inserm-00911037〉

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