title: Omeprazole, pantoprazole, and CYP2C19 effects on clopidogrel pharmacokinetic-pharmacodynamic relationships in stable coronary artery disease patients.
abstract: OBJECTIVE
  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).
  
  
  CONCLUSIONS
  This on/off shape explains that a small variation of exposure may have a clinical relevance.
authors.affiliation: Aix-Marseille Université, INSERM, UMR912 (SESSTIM), 13003, Marseille, France, nicolas.simon@ap-hm.fr.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Simon
authors.forename: Jonathan
authors.initials: J
authors.lastname: Finzi
authors.forename: Guillaume
authors.initials: G
authors.lastname: Cayla
authors.forename: Gilles
authors.initials: G
authors.lastname: Montalescot
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Collet
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Hulot
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D000328:Adult; D000483:Alleles; D000077144:Clopidogrel; D003324:Coronary Artery Disease / Q000188:drug therapy*; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics*; D004347:Drug Interactions; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009853:Omeprazole / Q000494:pharmacology* / Q000627:therapeutic use; D000077402:Pantoprazole; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D054328:Proton Pump Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D010975:Platelet Aggregation Inhibitors; D054328:Proton Pump Inhibitors; D000077144:Clopidogrel; D000077402:Pantoprazole; D065731:Cytochrome P-450 CYP2C19; D009853:Omeprazole; D013988:Ticlopidine