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Influence of CYP2C19 polymorphism on the pharmacokinetics of nelfinavir and its active metabolite
Author(s) -
Damle Bharat D.,
Uderman Howard,
Biswas Pinaki,
Crownover Penelope,
Lin Chang,
Glue Paul
Publication year - 2009
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2009.03499.x
Subject(s) - nelfinavir , pharmacokinetics , active metabolite , metabolite , cyp2c19 , pharmacology , medicine , confidence interval , pharmacogenetics , chemistry , genotype , biochemistry , virology , metabolism , cytochrome p450 , human immunodeficiency virus (hiv) , viral load , antiretroviral therapy , gene
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The true influence of CYP2C19*2 mutation on the pharmacokinetics of nelfinavir and its active metabolite, M8, is not clear. • 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 • The pharmacokinetics of nelfinavir was delineated using pharmacogenomic data from 66 healthy subjects. • 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. • 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.