Abstract 10673: Increased Clopidogrel Dose Overcomes CYP2C19 Poor Metabolizer Status
Carriers of the loss of function CYP2C19*2 variant (rs4244285) are less able to convert clopidogrel, a pro-drug, into its active metabolite, which results in diminished antiplatelet responses and higher cardiovascular event rates. We hypothesized that increasing the daily dose provided to poor metabolizers (PMs) can overcome the effect of this common variant. We studied 18 healthy Caucasian individuals (12 men and 6 women); mean age 42 years (range 33 - 66); six from each genotype group [*1/*1 extensive (EM), *1/*2 intermediate (IM), and *2/*2 (PM)]. Each PM was age- and sex- matched to an EM and IM. Participants received clopidogrel 75 mg for 8 days (period 1), 150 mg for 8 days (period 2), and 300 mg for 8 days (period 3) with 7 day washout between periods. ADP mediated (20 umol/L) platelet aggregation at 4 hours post dose on day 8 of each period and active metabolite pharmacokinetics over 4 hours on day 1 were evaluated. Baseline platelet aggregation did not differ among the groups before any dosing period (p>0.13). In each period, the genotype groups differed with respect to mean percent platelet aggregation at 4 hours (MPA4) and active metabolite area under the curve (AUC) (p<0.05 for all). MPA4 fell with increasing clopidogrel dose for each CYP2C19 group; PMs had higher mean platelet aggregation at each dose (Figure). At day 8, PMs on the 300 mg dose attain a comparable MPA4 to IMs on 150 mg and EMs on the 75 mg dose (32.6%, 33.2%, 31.3%, respectively) (Figure). Exposure to the active metabolite was higher in EMs compared to PMs at each dose; PMs receiving the 300 mg dose experience exposure similar to EMs on 75 mg (AUC 37.7 and 33.5 ng.h/ml, respectively) (Figure). In conclusion, dosing with clopidogrel 300 mg allows PMs to attain levels of metabolite and platelet aggregation equivalent to 75 mg in EMs, suggesting alternate mechanisms for clopidogrel activation in PMs. Dosing strategies in outcomes trials that use 150 mg may not be adequate to overcome the effect of CYP2C19*2 in PMs.
- © 2011 by American Heart Association, Inc.