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Omeprazole, pantoprazole, and CYP2C19 effects on clopidogrel pharmacokinetic-pharmacodynamic relationships in stable coronary artery disease patients
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Omeprazole, pantoprazole, and CYP2C19 effects on clopidogrel pharmacokinetic-pharmacodynamic relationships in stable coronary artery disease patients
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Journal Article
Omeprazole, pantoprazole, and CYP2C19 effects on clopidogrel pharmacokinetic-pharmacodynamic relationships in stable coronary artery disease patients
2015
Overview
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 P2Y
12
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%; E
AUC50
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.
Publisher
Springer Berlin Heidelberg,Springer Nature B.V,Springer Verlag
Subject
2-Pyridinylmethylsulfinylbenzimidazoles - pharmacology
/ 2-Pyridinylmethylsulfinylbenzimidazoles - therapeutic use
/ Adult
/ Alleles
/ Biomedical and Life Sciences
/ Coronary Artery Disease - drug therapy
/ Cytochrome P-450 CYP2C19 - genetics
/ Female
/ Genotype
/ Humans
/ Kinetics
/ Male
/ Omeprazole - therapeutic use
/ Platelet Aggregation - drug effects
/ Platelet Aggregation Inhibitors - pharmacokinetics
/ Platelet Aggregation Inhibitors - pharmacology
/ Platelet Aggregation Inhibitors - therapeutic use
/ Proton Pump Inhibitors - pharmacology
/ Proton Pump Inhibitors - therapeutic use
/ Ticlopidine - analogs & derivatives
