title: The effect of CYP2C19 gene polymorphisms on the pharmacokinetics and pharmacodynamics of prasugrel 5-mg, prasugrel 10-mg and clopidogrel 75-mg in patients with coronary artery disease.
abstract: CYP2C19 genotype has been shown to impact response to clopidogrel 75-mg but not prasugrel 10-mg. Here, we assessed effects of CYP2C19 metaboliser status on pharmacokinetics (PK) and pharmacodynamic (PD) responses to prasugrel 5-mg and 10-mg and clopidogrel 75-mg using data from two PK/PD studies in stable coronary artery disease (CAD) patients (GENERATIONS and FEATHER). Active metabolite concentrations (area under the curve, AUC[0-tlast]), maximum platelet aggregation (MPA) measured by light transmission aggregometry, vasodilator-stimulated phosphoprotein platelet reactivity index, and VerifyNow P2Y12-platelet reaction units (VN-PRU) were analysed by CYP2C19-predicted phenotype (extensive metaboliser [EM; N=154], *2-*8 non-carriers, vs reduced metaboliser [RM; N=41],*2-*8 carriers/*17 non-carriers). AUC(0-tlast) was unaffected by metaboliser status for prasugrel 5-mg and 10-mg (geometric mean EM/RM ratios 1.00, 95% confidence interval [CI]: 0.86,1.17, p>0.99; and 0.97, 95% CI:0.85,1.12, p=0.71, respectively), but was lower among RMs receiving clopidogrel 75-mg (1.37, 95% CI:1.14,1.65, p<0.001). Platelet reactivity was not significantly affected by CYP2C19 metaboliser status for prasugrel 5-mg, or for prasugrel 10-mg by MPA and VN-PRU, but for clopidogrel 75-mg was significantly higher in reduced metabolisers (all measures p<0.01). Prasugrel 10-mg showed greater antiplatelet effects vs clopidogrel 75-mg (all comparisons p<0.001). Prasugrel 5-mg showed greater antiplatelet effects vs clopidogrel 75-mg in RMs (all p<0.001), and comparable effects in EMs (all p≥0.37). In contrast to clopidogrel, prasugrel active metabolite PK was not influenced by CYP2C19 genotype. Antiplatelet effect for prasugrel 10-mg was greater irrespective of metaboliser status and for prasugrel 5-mg was greater for RMs and comparable for EMs as compared to clopidogrel 75-mg.
authors.affiliation: Paul A. Gurbel, MD, Sinai Center for Thrombosis Research, Cardiac Catheterization Laboratory, 2401 W. Belvedere Ave, Baltimore, MD 21215, USA, Tel.: +1 410 601 9600, Fax: +1 410 601 9601, E-mail: PGURBEL@LIFEBRIDGEHEALTH.ORG.
authors.forename: P A
authors.initials: PA
authors.lastname: Gurbel
authors.forename: T O
authors.initials: TO
authors.lastname: Bergmeijer
authors.forename: U S
authors.initials: US
authors.lastname: Tantry
authors.forename: J M
authors.initials: JM
authors.lastname: ten Berg
authors.forename: D J
authors.initials: DJ
authors.lastname: Angiolillo
authors.forename: S
authors.initials: S
authors.lastname: James
authors.forename: T L
authors.initials: TL
authors.lastname: Lindahl
authors.forename: P
authors.initials: P
authors.lastname: Svensson
authors.forename: J A
authors.initials: JA
authors.lastname: Jakubowski
authors.forename: P B
authors.initials: PB
authors.lastname: Brown
authors.forename: S
authors.initials: S
authors.lastname: Duvvuru
authors.forename: S
authors.initials: S
authors.lastname: Sundseth
authors.forename: J R
authors.initials: JR
authors.lastname: Walker
authors.forename: D
authors.initials: D
authors.lastname: Small
authors.forename: B A
authors.initials: BA
authors.lastname: Moser
authors.forename: K J
authors.initials: KJ
authors.lastname: Winters
authors.forename: D
authors.initials: D
authors.lastname: Erlinge
mesh_terms: D000368:Aged; D002985:Clinical Protocols; D000077144:Clopidogrel; D003324:Coronary Artery Disease / Q000188:drug therapy* / Q000235:genetics; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D010879:Piperazines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010974:Platelet Aggregation / Q000187:drug effects / Q000235:genetics; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011110:Polymorphism, Genetic; D000068799:Prasugrel Hydrochloride; D013876:Thiophenes / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D013876:Thiophenes; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19; D000068799:Prasugrel Hydrochloride; D013988:Ticlopidine
keywords: CYP2C19; Prasugrel; clopidogrel; coronary artery disease; platelet reactivity