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.
RCT Entities:
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 infarctionpatients 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.
Authors: J-S Hulot; G Wuerzner; C Bachelot-Loza; M Azizi; A Blanchard; S Peyrard; C Funck-Brentano; P Gaussem Journal: J Thromb Haemost Date: 2009-12-21 Impact factor: 5.824
Authors: Wayne A Ray; Katherine T Murray; Marie R Griffin; Cecilia P Chung; Walter E Smalley; Kathi Hall; James R Daugherty; Lisa A Kaltenbach; C Michael Stein Journal: Ann Intern Med Date: 2010-03-16 Impact factor: 25.391
Authors: Dirk Sibbing; Tanja Morath; Julia Stegherr; Siegmund Braun; Wolfgang Vogt; Martin Hadamitzky; Albert Schömig; Adnan Kastrati; Nicolas von Beckerath Journal: Thromb Haemost Date: 2009-04 Impact factor: 5.249
Authors: Alan R Shuldiner; Jeffrey R O'Connell; Kevin P Bliden; Amish Gandhi; Kathleen Ryan; Richard B Horenstein; Coleen M Damcott; Ruth Pakyz; Udaya S Tantry; Quince Gibson; Toni I Pollin; Wendy Post; Afshin Parsa; Braxton D Mitchell; Nauder Faraday; William Herzog; Paul A Gurbel Journal: JAMA Date: 2009-08-26 Impact factor: 56.272