Influence of CYP2C19 polymorphism on the pharmacokinetics of nelfinavir and its active metabolite

center dot The true influence of CYP2C19*2 mutation on the pharmacokinetics of nelfinavir and its active metabolite, M8, is not clear. center dot Often, published studies have combined *2 hetero- and homozygous poor metabolizers (PMs) and/or have very limited data from *2 homozygotes, which contributes to the lack of clarity. WHAT THIS STUDY ADDS center dot The pharmacokinetics of nelfinavir was delineated using pharmacogenomic data from 66 healthy subjects. center dot The exposure of nelfinavir was elevated, whereas that of M8 was reduced, in heterozygous and homozygous PMs in an incremental manner consistent with the loss of functional alleles. center dot However, the exposure of active moiety was only modestly elevated in hetero- and homozygous PMs. AIMS This study reports the pharmacokinetics of nelfinavir, its active metabolite, M8, and active moiety (nelfinavir + M8) in volunteers genotyped for CYP2C19 as extensive metabolizer (*1*1; n = 38), heterozygous poor metabolizer (PM) (*1*2; n = 22) and homozygous PM (*2*2; n = 6). METHODS Subjects received nelfinavir at normal dose (3.5 days of 1250 mg q12h) or high dose (1250 mg q12h for 3 days and single dose of 3125 mg on day 4). Steady-state plasma samples were analysed by high-performance liquid chromatography/ultraviolet assay to determine pharmacokinetics. RESULTS At steady state, the mean C(max) was 42% [95% confidence interval (CI) 19, 69] and 63% (95% CI 20, 122) higher, and mean AUC was 51% (95% CI 24, 83) and 85% (95% CI 32, 159) higher for *1*2 and *2*2 compared with *1*1 subjects, respectively. For M8, the mean C(max) and AUC were 35% (95% CI 6, 55) and 33% (95% CI -3, 56), respectively, lower for *1*2 compared with *1*1 subjects. M8 was not detectable in *2*2 subjects. The mean C(max) and AUC values for the active moiety were higher by 30-35% for the *1*2 and *2*2 compared with *1*1 subjects. CONCLUSIONS Mutation in CYP2C19 increased the systemic exposure of nelfinavir and reduced the exposure of M8. No significant differences were noted among the heterozygous (*1*2) and homozygous (*2*2) PMs. These changes are not considered to be clinically relevant and hence the use of nelfinavir does not require prior assessment of CYP2C19 genotype.