Abstract 17693: Genetic Polymorphism and the Impact of a Higher Clopidogrel Dose Regimen on Active Metabolite Exposure and Antiplatelet Response in Healthy Subjects
Objective: To evaluate whether high-dose clopidogrel (600-mg loading/150 mg/day) overcomes reduced pharmacokinetic and pharmacodynamic response in subjects with CYP2C19 loss-of-function alleles treated with clopidogrel 300-mg loading/75 mg/day.
Methods: Pharmacokinetic and pharmacodynamic evaluations were performed in a randomized, double-blind, crossover study conducted in ultrarapid metabolizers (UMs; *1/*17 and *17/*17), extensive metabolizers (EMs; *1/*1), intermediate metabolizers (IMs; *1/*2 and *1/*3), and poor metabolizers (PMs; *2/*2 and *2/*3). Consecutive healthy male or female subjects with alleles *1, *2, *3 or *17 were randomized to standard-dose clopidogrel (clopidogrel 300-mg loading dose/75 mg/day for 4 days) followed by high-dose clopidogrel, or vice versa, until 10 subjects were enrolled per metabolizer group. Clopidogrel active metabolite isomer H4 (clopi-H4) was assessed by liquid chromatography-tandem mass spectrometry. Platelet function was assessed by light transmittance aggregometry using 5 μM ADP.
Results: Clopi-H4 exposure decreased by 71% (75 mg/day) and 64% (150 mg/day) in PMs versus EMs. Differences in maximal platelet aggregation in PMs versus EMs were 10.5% (75 mg/day) and 7.9% (150 mg/day). In PMs, 600 mg/150 mg/day resulted in clopi-H4 exposure and antiplatelet responses closer to EMs given 300 mg/75 mg/day. In a pooled analysis of 396 healthy subjects enrolled in the present study and 6 further Phase I studies, performed to replicate the CYP2C19 analysis and evaluate CYP1A2, CYP2C9, CYP2B6, CYP3A5, CYP2D6, ABCB1, and P2RY12 polymorphisms, only CYP2C19 had a highly statistically significant effect on clopi-H4 formation and antiplatelet response.
Conclusions: Individuals with two loss-of-function CYP2C19 alleles retain the capacity to activate clopidogrel, but only approximately 50% as efficiently as those with at least one active allele. Doubling the loading- and maintenance-doses of clopidogrel partially restores clopi-H4 exposure and brings the antiplatelet response closer to that observed with standard clopidogrel dosing in patients with more common CYP2C19 genotypes.
- © 2010 by American Heart Association, Inc.