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

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 (11; n = 38), heterozygous poor metabolizer (PM) (12; n = 22) and homozygous PM (22; 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 12 and 22 compared with 11 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 12 compared with 11 subjects. M8 was not detectable in 22 subjects. The mean C(max) and AUC values for the active moiety were higher by 30-35% for the 12 and 22 compared with 11 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 (12) and homozygous (22) PMs. These changes are not considered to be clinically relevant and hence the use of nelfinavir does not require prior assessment of CYP2C19 genotype.