title: Active metabolite concentration of clopidogrel in patients taking different doses of aspirin: results of the interaction trial.
abstract: BACKGROUND
  The CURRENT-OASIS-7 and PLATO trials suggest that the benefit of clopidogrel is influenced by the dose of aspirin.
  
  
  OBJECTIVE
  To explore a potential pharmacokinetic interaction between aspirin and clopidogrel, and determinants of clopidogrel active metabolite (AM) levels.
  
  
  METHODS
  In part 1, using a 2 × 2 factorial design, we randomized patients to clopidogrel 600 mg loading dose (LD) followed by 150 mg day(-1) for 6 days and 75 mg day(-1) thereafter, or clopidogrel 300 mg LD followed by 75 mg day(-1) thereafter, and compared aspirin at 325 mg or 81 mg day(-1) . In part 2, patients were given a 600-mg clopidogrel LD, and were randomly allocated to aspirin 325 mg or 81 mg day(-1) . We combine the data from the two parts. Blood samples were collected 1 h after administration of the study drug.
  
  
  RESULTS
  We randomized 302 patients (mean age 60.4 ± 9.9 years). Clopidogrel AM levels were similar in patients randomized to aspirin 325 or 81 mg (geometric mean, 12.70 ng mL(-1) ; 95% CI, 10.96-14.72 ng mL(-1) ; and geometric mean, 12.55 ng mL(-1) ; 95% CI, 10.80-14.58 ng mL(-1) ; P = 0.91). Blood levels of clopidogrel were lower in CYP2C19*2 loss-of-function (LOF) carriers compared with non-carriers (10.72 ng mL(-1) ; 95% CI, 8.83-13.01 ng mL(-1) ; and 15.21 ng mL(-1) ; 95% CI, 13.30-17.40 ng mL(-1) , respectively; P = 0.003) whereas levels in gain of function carriers and non-carriers were similar (13.31 ng mL(-1) ; 95% CI, 11.53-15.35 ng mL(-1) ; and 14.07 ng mL(-1) ; 95% CI, 11.74-16.87 ng mL(-1) , respectively; P = 0.4). Independent baseline predictors of clopidogrel AM levels were LOF genotype, body mass index, diabetes, proton pump inhibitor use and creatinine clearance, but accounted for only 20% of the variability in levels.
  
  
  CONCLUSIONS
  Aspirin dose does not predict clopidogrel AM levels 1 h post-LD. Most of the variability in clopidogrel AM levels is not explained by patient characteristics or CYP2C19 metabolizer status.
authors.affiliation: Department of Emergency Medicine, Cardiovascular Institute and Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, National Center for Cardiovascular Disease, Beijing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Liang
authors.forename: J
authors.initials: J
authors.lastname: Hirsh
authors.forename: J I
authors.initials: JI
authors.lastname: Weitz
authors.forename: D
authors.initials: D
authors.lastname: Sloane
authors.forename: P
authors.initials: P
authors.lastname: Gao
authors.forename: G
authors.initials: G
authors.lastname: Pare
authors.forename: J
authors.initials: J
authors.lastname: Zhu
authors.forename: J W
authors.initials: JW
authors.lastname: Eikelboom
mesh_terms: D065767:Activation, Metabolic; D000368:Aged; D001241:Aspirin / Q000008:administration & dosage*; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics / Q000378:metabolism; D004334:Drug Administration Schedule; D004347:Drug Interactions; D016903:Drug Monitoring / Q000379:methods; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D012307:Risk Factors; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics
chemical_list: D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine; D001241:Aspirin
keywords: aspirin; clopidogrel; drug interactions; genetic polymorphisms; pharmacokinetics