title: Clopidogrel pharmacodynamics and pharmacokinetics in the fed and fasted state: a randomized crossover study of healthy men.
abstract: Clopidogrel requires CYP450-mediated hepatic metabolism to form its active metabolite (clopi-H4). This randomized, placebo-controlled, crossover study was designed to characterize the effect of a high-fat or standard breakfast on adenosine diphosphate (ADP)-induced platelet aggregation and exposure to unchanged clopidogrel and clopi-H4 following clopidogrel (300-mg loading dose, 75 mg/d for 4 days) in 72 healthy men. At day 5 and as assessed by liquid chromatography-tandem mass spectrometry, unchanged clopidogrel area under the concentration- time curve from 0 to 24 hours (AUC(0-24)) increased 3.32-fold (90% confidence interval [CI], 2.88-3.84), and clopi-H4 AUC(0-24) decreased nonsignificantly by 12% (90% CI, 0.82-0.94) upon administration of clopidogrel with a standard breakfast. The estimated treatment difference in maximum platelet aggregation (MPA) induced by ADP 5 µM and assessed by light transmission aggregometry was 4.7%, with the 90% CI (0.9%-8.5%) contained within the prespecified equipotency range of ±15%. The mean ± standard deviation of day 5 inhibition of platelet aggregation was 49.7% ± 17.2% and 54.0% ± 13.3% in the fed and fasted states, respectively. Despite increased unchanged clopidogrel and slightly decreased clopi-H4 exposure following clopidogrel administration, the numerical increase in MPA in the fed versus fasted state was small and within the prespecified limit of equipotency. These findings confirm that clopidogrel can be taken with or without food.
authors: DSAR–Drug Disposition, sanofi-aventis Recherche Développement, Montpellier, France. Fabrice.Hurbin@sanofi-aventis.com
authors: Fabrice
authors: F
authors: Hurbin
authors: Xavier
authors: X
authors: Boulenc
authors: Nikki
authors: N
authors: Daskalakis
authors: Christine
authors: C
authors: Farenc
authors: Theresa
authors: T
authors: Taylor
authors: Damien
authors: D
authors: Bonneau
authors: Frank
authors: F
authors: Lacreta
authors: Sue
authors: S
authors: Cheng
authors: Eric
authors: E
authors: Sultan
mesh_terms: D000244:Adenosine Diphosphate; D000328:Adult; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D062408:Breakfast; D000077144:Clopidogrel; D018592:Cross-Over Studies; D065731:Cytochrome P-450 CYP2C19; D059305:Diet, High-Fat; D018565:Food-Drug Interactions; D005838:Genotype; D006801:Humans; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D055815:Young Adult
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