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Arch Cardiovasc Dis. 2013 Dec;106(12):661-71. doi: 10.1016/j.acvd.2013.09.002. Epub 2013 Nov 15.

Effects of rabeprazole on the antiplatelet effects and pharmacokinetics of clopidogrel in healthy volunteers.

Author information

1
Inserm, CIC-9304 and UMRS-956, Paris, France; AP-HP, Pitié-Salpêtrière Hospital, Department of Pharmacology and CIC-9304, Paris, France; UPMC Univ Paris 06, Faculty of Medicine, Department of Pharmacology and UMRS-956, Paris, France. Electronic address: christian.funck-brentano@upmc.fr.

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 (75 mg/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.

KEYWORDS:

ADP; CYP; CYP2C19; CYP2C19 protein; Clopidogrel; Drug interactions; EM; IPA; Inhibiteurs de pompes à protons; Interactions médicamenteuses; MFI; MPA; PGE1; PPI; PRI; Proton-pump inhibitors; Protéine VASP; VASP; Vasodilator-stimulated phosphoprotein; adenosine diphosphate; cytochrome P-450; extensive metabolizer; inhibition of platelet aggregation; maximal platelet aggregation; mean fluorescence intensity; platelet reactivity index; prostaglandin E1; proton-pump inhibitors; vasodilator-stimulated phosphoprotein

PMID:
24246616
DOI:
10.1016/j.acvd.2013.09.002
[Indexed for MEDLINE]
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