Key result
CYP2C19*17 carriers had higher percentage inhibition of platelet aggregation than non-carriers (84% and 73% vs 63%, P=0.014) after 600 mg clopidogrel, but no difference in absolute aggregation.
Why the study?
Does the CYP2C19*17 genotype alter the pharmacokinetics and pharmacodynamics of clopidogrel in healthy male volunteers?
Does the CYP2C19*17 genotype alter the pharmacokinetics and pharmacodynamics of clopidogrel in healthy male volunteers?
Carriers of the CYP2C19*17 allele exhibit higher percentage inhibition of platelet aggregation after a 600 mg clopidogrel loading dose, though absolute platelet aggregation and active metabolite exposure are not significantly altered.
Answers are grounded in this paper and cite their sources.
CYP2C19*17 genotype was associated with altered clopidogrel response in volunteers; leaves open clinical outcome impact.
The aim of the present study was to determine the impact of CYP2C19*17 on the pharmacokinetics and pharmacodynamics of the active metabolite of clopidogrel and the pharmacokinetics of proguanil. Thus, we conducted an open-label two-phase cross-over study in 31 healthy male volunteers (11 CYP2C19*1/*1, 11 CYP2C19*1/*17 and nine CYP2C19*17/*17). In Phase A, the pharmacokinetics of the derivatized active metabolite of clopidogrel (CAMD) and platelet function were determined after administration of a single oral dose of 600 mg clopidogrel (Plavix; Sanofi-Avensis, Horsholm, Denmark). In Phase B, the pharmacokinetics of proguanil and its metabolites cycloguanil and 4-chlorphenylbiguanide (4-CPB) were determined in 29 of 31 subjects after a single oral dose of 200 mg proguanil given as the combination drug Malarone (GlaxoSmithKline Pharma, Brondby, Denmark). Significant correlations were found between the area under the time-concentration curve (AUC0-∞ ) of CAMD and both the absolute ADP-induced P2Y12 receptor-activated platelet aggregation (r = -0.60, P = 0.0007) and the percentage inhibition of aggregation (r = 0.59, P = 0.0009). In addition, the CYP2C19*17/*17 and CYP2C19*1/*17 genotype groups had significantly higher percentage inhibition of platelet aggregation compared with the CYP2C19*1/*1 subjects (geometric mean percentage inhibition of 84%, 73% and 63%, respectively; P = 0.014). Neither the absolute ADP-induced P2Y12 receptor-activated platelet aggregation, exposure to CAMD nor the pharmacokinetic parameters of proguanil, cycloguanil and 4-CPB exhibited any significant differences among the genotype groups. In conclusion, carriers of CYP2C19*17 exhibit higher percentage inhibition of platelet aggregation, but do not have significantly lower absolute P2Y12 receptor-activated platelet aggregation or higher exposure to the active metabolite after a single oral administration of 600 mg clopidogrel.
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Pedersen et al. (2014) studied Healthy (n=31). CYP2C19*17 genotype vs. CYP2C19*1/*1 genotype was evaluated on Percentage inhibition of platelet aggregation (p=0.014). CYP2C19*17 carriers had higher percentage inhibition of platelet aggregation than non-carriers (84% and 73% vs 63%, P=0.014) after 600 mg clopidogrel, but no difference in absolute aggregation.
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