Influence of CYP2C19 polymorphism on the pharmacokinetics of nelfinavir and its active metabolite.
OBJECTIVE
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.
Damle
Bharat D
BD
Pfizer Inc., Global Medical Research & Development, 685 Third Avenue, 685/13/55, New York, NY 10017, USA. bharat.damle@pfizer.com
Uderman
Howard
H
Biswas
Pinaki
P
Crownover
Penelope
P
Lin
Chang
C
Glue
Paul
P
D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000493:pharmacokinetics*; D065731:Cytochrome P-450 CYP2C19; D005260:Female; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate / Q000235:genetics; D008875:Middle Aged; D019888:Nelfinavir / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D011110:Polymorphism, Genetic; D055815:Young Adult
D017320:HIV Protease Inhibitors; C517960:M8-nelfinavir; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D019888:Nelfinavir