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


OBJECTIVE
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.
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.
Christian
C
Funck-Brentano
Jean
J
Szymezak
Olivier
O
Steichen
Dominique
D
Ducint
Mathieu
M
Molimard
Véronique
V
Remones
Michel
M
Azizi
Pascale
P
Gaussem
D000328:Adult; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D001711:Biotransformation; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000097:blood; D000077144:Clopidogrel; D018592:Cross-Over Studies; D065731:Cytochrome P-450 CYP2C19; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D006207:Half-Life; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008840:Microfilament Proteins / Q000097:blood; D009853:Omeprazole / Q000008:administration & dosage; D010297:Paris; D010750:Phosphoproteins / Q000097:blood; D010766:Phosphorylation; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010979:Platelet Function Tests; D011446:Prospective Studies; D054328:Proton Pump Inhibitors / Q000008:administration & dosage*; D064750:Rabeprazole / Q000008:administration & dosage*; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000098662:Vasodilator-Stimulated Phosphoprotein
D015815:Cell Adhesion Molecules; D004791:Enzyme Inhibitors; D008840:Microfilament Proteins; D010750:Phosphoproteins; D010975:Platelet Aggregation Inhibitors; D054328:Proton Pump Inhibitors; D000098662:Vasodilator-Stimulated Phosphoprotein; D064750:Rabeprazole; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D009853:Omeprazole; D013988:Ticlopidine
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