title: Pharmacokinetics and pharmacodynamics following maintenance doses of prasugrel and clopidogrel in Chinese carriers of CYP2C19 variants.
abstract: OBJECTIVE
  This open-label, two-period, randomized, crossover study was designed to determine the effect of CYP2C19 reduced function variants on exposure to active metabolites of, and platelet response to, prasugrel and clopidogrel.
  
  
  METHODS
  Ninety healthy Chinese subjects, stratified by CYP2C19 phenotype, were randomly assigned to treatment with prasugrel 10 mg or clopidogrel 75 mg for 10 days followed by 14 day washout and 10 day treatment with the other drug. Eighty-three subjects completed both treatment periods. Blood samples were collected at specified time points for measurement of each drug's active metabolite (Pras-AM and Clop-AM) concentrations and determination of inhibition of platelet aggregation (IPA) by light transmittance aggregometry. CYP2C19 genotypes were classified into three predicted phenotype groups: rapid metabolizers [RMs (*1/*1)], heterozygous or intermediate metabolizers [IMs (*1/*2, *1/*3)] and poor metabolizers [PMs (*2/*2, *2/*3)].
  
  
  RESULTS
  Pras-AM exposure was similar in IMs and RMs (90% CI 0.85, 1.03) and slightly lower in PMs than IMs (90% CI 0.74, 0.99), whereas Clop-AM exposure was significantly lower in IMs compared with RMs (90% CI 0.62, 0.83), and in PMs compared with IMs (90% CI 0.53, 0.82). IPA was more consistent among RMs, IMs and PMs in prasugrel treated subjects (80.2%, 84.2% and 80.2%, respectively) than in clopidogrel treated subjects (59.7%, 56.2% and 36.8%, respectively; P < 0.001).
  
  
  CONCLUSIONS
  Prasugrel demonstrated higher active metabolite exposure and more consistent pharmacodynamic response across all three predicted phenotype groups compared with clopidogrel, confirming observations from previous research that CYP2C19 phenotype plays an important role in variability of response to clopidogrel, but has no impact on response to prasugrel.
authors.affiliation: Lilly-NUS Centre for Clinical Pharmacology, Singapore. ronan.kelly@lilly.com
authors.forename: Ronan P
authors.initials: RP
authors.lastname: Kelly
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Close
authors.forename: Nagy A
authors.initials: NA
authors.lastname: Farid
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Winters
authors.forename: Lei
authors.initials: L
authors.lastname: Shen
authors.forename: Fanni
authors.initials: F
authors.lastname: Natanegara
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Jakubowski
authors.forename: Mary
authors.initials: M
authors.lastname: Ho
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Walker
authors.forename: David S
authors.initials: DS
authors.lastname: Small
mesh_terms: D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D000077144:Clopidogrel; D018592:Cross-Over Studies; D065731:Cytochrome P-450 CYP2C19; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D010375:Pedigree; D010879:Piperazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects* / Q000235:genetics; D010975:Platelet Aggregation Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D011110:Polymorphism, Genetic / Q000235:genetics; D000068799:Prasugrel Hydrochloride; D058921:Purinergic P2Y Receptor Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D013876:Thiophenes / Q000493:pharmacokinetics / Q000494:pharmacology*; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D055815:Young Adult
chemical_list: D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D013876:Thiophenes; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D000068799:Prasugrel Hydrochloride; D013988:Ticlopidine