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

  • Pharmacodynamics
  • Published:
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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.

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Abbreviations

AUC0-6 :

Area Under the plasma concentration-time Curve from time of dose (0) to 6-h

Cmax:

Maximal plasma concentration

Clopi-H4:

Clopidogrel active metabolite isomer H4

CYP2C19:

Cytochrome P450-2C19

IPA:

Inhibition of platelet aggregation

LC/MS/MS:

Liquid chromatography tandem mass spectrometry

LD:

Loading dose

LTA:

Light transmission aggregometry

MACE:

Major adverse cardiac event

MD:

Maintenance dose

MI:

Myocardial infarction

PCI:

Percutaneous coronary intervention

PD:

Pharmacodynamic

PK:

Pharmacokinetic

POC:

Point of care assay

PON1:

Paraoxonase-1

PRU:

Platelet reaction unit

RPA:

Residual platelet aggregation

VN-P2Y12 :

VerifyNow™ P2Y12

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Conflict of interest

The authors declare no competing interest.

Authors’ contributions

N. Simon wrote the manuscript and performed the analysis.

J. Finzi, G. Cayla, and G. Montalescot designed and performed the research.

J-P. Collet and J-S. Hulot wrote the manuscript, and designed and performed the research.

Author information

Authors and Affiliations

  1. Aix-Marseille Université, INSERM, UMR912 (SESSTIM), 13003, Marseille, France

    Nicolas Simon

  2. Service de Pharmacologie Clinique, Centre Anti-Poison, AP-HM, Hôpital Sainte Marguerite, F-13274, Marseille, France

    Nicolas Simon

  3. UPMC Univ Paris 06, Faculty of Medicine, UMRS_1166-ICAN, Institute of Cardiometabolism and Nutrition, Sorbonne Universités, F-75013, Paris, France

    Jonathan Finzi, Guillaume Cayla, Gilles Montalescot, Jean-Philippe Collet & Jean-Sébastien Hulot

  4. Cardiology Institute, AP-HP, Pitié-Salpêtrière Hospital, F-75013, Paris, France

    Jonathan Finzi, Guillaume Cayla, Gilles Montalescot, Jean-Philippe Collet & Jean-Sébastien Hulot

  5. INSERM, UMRS_1166-ICAN, F-75013, Paris, France

    Jonathan Finzi, Guillaume Cayla, Gilles Montalescot, Jean-Philippe Collet & Jean-Sébastien Hulot

  6. Faculté de Médecine, Service de pharmacologie clinique, 27 Bd Jean Moulin, 13385, Marseille, France

    Nicolas Simon

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Simon, N., Finzi, J., Cayla, G. et al. Omeprazole, pantoprazole, and CYP2C19 effects on clopidogrel pharmacokinetic-pharmacodynamic relationships in stable coronary artery disease patients. Eur J Clin Pharmacol 71, 1059–1066 (2015). https://doi.org/10.1007/s00228-015-1882-3

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  • DOI: https://doi.org/10.1007/s00228-015-1882-3

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