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Eur J Clin Pharmacol. 2015 Sep;71(9):1059-66. doi: 10.1007/s00228-015-1882-3. Epub 2015 Jun 14.

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

Author information

1
Aix-Marseille Université, INSERM, UMR912 (SESSTIM), 13003, Marseille, France, nicolas.simon@ap-hm.fr.

Abstract

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.

PMID:
26071277
DOI:
10.1007/s00228-015-1882-3
[Indexed for MEDLINE]

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