Article date: November 2009
By: Bharat D. Damle, Howard Uderman, Pinaki Biswas, Penelope Crownover, Chang Lin, Paul Glue, in Volume 68, Issue 5, pages 682-689
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
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 Cmax 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 Cmax 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 Cmax 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.
DOI: 10.1111/j.1365-2125.2009.03499.x
View this article