title: High doses of clopidogrel to overcome genetic resistance: the randomized crossover CLOVIS-2 (Clopidogrel and Response Variability Investigation Study 2).
abstract: OBJECTIVE
  This study sought to determine whether the pharmacokinetic (PK) and pharmacodynamic (PD) responses to high or standard clopidogrel loading doses (LDs) differ according to CYP2C19*2 allele.
  
  
  BACKGROUND
  CYP2C19 loss-of-function alleles are associated with reduced responsiveness to standard clopidogrel doses.
  
  
  METHODS
  Young post-myocardial infarction patients heterozygous (wild type [wt]/*2, n = 43) or homozygous (*2/*2, n = 8) 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 LD. The relative reduction in residual platelet aggregation (RR-RPA, %) and the area under the plasma concentration time curve of active metabolite from baseline to 6 h after loading (AUC(0-6)) were compared according to both LD and CYP2C19*2 carriage.
  
  
  RESULTS
  The 300-mg LD led to a gene-dose effect for RR-RPA (-65.7% ± 35.9% in wt/wt vs. -48.0% ± 38.4% in wt/*2 vs. -14.6% ± 32.4% in *2/*2; overall p value = 0.003, p = 0.03 for wt/wt versus wt/*2, p = 0.04 for wt/*2 versus *2/*2) with minor effect in *2/*2 carriers. After the 900-mg LD, the effect of the CYP2C19*2 variant on platelet inhibition was fully compensated in wt/*2 carriers but not in *2/*2 carriers (-83.6% ± 25.8% in wt/wt vs.-77.2% ± 26.9% in wt/*2 vs. -29.5% ± 26.8% in *2/*2; overall p value = 0.0003, p = 0.20 for wt/wt versus wt/*2, p < 0.001 for wt/*2 versus *2/*2). A similar pattern was observed for the active metabolite AUC(0-6) according to carriage of CYP2C19*2 for both LDs. There was a significant correlation between PK and PD responses irrespective of the LD.
  
  
  CONCLUSIONS
  Carriers of CYP2C19*2 display significantly lower responses to clopidogrel with a gene-dose effect. Clopidogrel resistance can be overcome by increasing the dose in heterozygous carriers but not in homozygous carriers. (Clopidogrel and Response Variability Investigation Study 2 [CLOVIS-2]; NCT00822666).
authors.affiliation: Institut de Cardiologie, INSERM CMR937, Hôpital Pitié-Salpêtrière (Assistance Publique-Hôpitaux de Paris), Université Pierre et Marie Curie (UPMC, Paris VI), Paris, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Collet
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Hulot
authors.forename: Ghalia
authors.initials: G
authors.lastname: Anzaha
authors.forename: Ana
authors.initials: A
authors.lastname: Pena
authors.forename: Thomas
authors.initials: T
authors.lastname: Chastre
authors.forename: Claire
authors.initials: C
authors.lastname: Caron
authors.forename: Johanne
authors.initials: J
authors.lastname: Silvain
authors.forename: Guillaume
authors.initials: G
authors.lastname: Cayla
authors.forename: Anne
authors.initials: A
authors.lastname: Bellemain-Appaix
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Vignalou
authors.forename: Sophie
authors.initials: S
authors.lastname: Galier
authors.forename: Olivier
authors.initials: O
authors.lastname: Barthélémy
authors.forename: Farzin
authors.initials: F
authors.lastname: Beygui
authors.forename: Vanessa
authors.initials: V
authors.lastname: Gallois
authors.forename: Gilles
authors.initials: G
authors.lastname: Montalescot
mesh_terms: D000244:Adenosine Diphosphate; D000328:Adult; D015906:Angioplasty, Balloon, Coronary / Q000009:adverse effects; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D000077144:Clopidogrel; D001026:Coronary Artery Bypass / Q000009:adverse effects; D018592:Cross-Over Studies; D065731:Cytochrome P-450 CYP2C19; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D005602:France; D018628:Gene Dosage; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000097:blood / Q000628:therapy*; D010641:Phenotype; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D010979:Platelet Function Tests; D011237:Predictive Value of Tests; D011446:Prospective Studies; D012042:Registries; D018570:Risk Assessment; D012307:Risk Factors; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D010975:Platelet Aggregation Inhibitors; D000244:Adenosine Diphosphate; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine