Omeprazole, pantoprazole, and CYP2C19 effects on clopidogrel pharmacokinetic-pharmacodynamic relationships in stable coronary artery disease patients.

PURPOSE: Proton-pump Inhibitors use and CYP2C19 loss-of-function alleles are associated with reduced responsiveness to standard clopidogrel doses and increased cardiovascular events. METHODS: Post-myocardial infarction patients heterozygous (wild type [wt]/*2, n = 41) or homozygous (*2/*2, n = 7) for the CYP2C19*2 genetic variant were matched with patients not carrying the variant (wt/wt, n = 58). All patients were randomized to a 300- or 900-mg clopidogrel loading dose. A PK/PD model was defined using the variation of the P2Y12 reaction unit relative to baseline. RESULTS: Carriage of CYP2C19*2 allele and the use of omeprazole/esomeprazole were associated with the inter-individual variability in the active metabolite clearance. The relationship between inhibition of platelet aggregation (IPA, %) and the active metabolite AUC (h*µg/L) was described by a sigmoid function (Emax 56 ± 5%; EAUC50 15.9 ± 0.8 h*µg/L) with a gamma exponent (7.04 ± 2.26). CONCLUSION: This on/off shape explains that a small variation of exposure may have a clinical relevance.