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

Authors


  • P.G. present address: Dunedin School of Medicine, Dunedin, New Zealand.

Dr Bharat D. Damle, PhD, Pfizer Inc., Global Medical Research & Development, 685 Third Avenue, 685/13/55, New York, NY 10017, USA.
Tel: + 1 212 733 4739
Fax: + 1 646 441 4493
E-mail: bharat.damle@pfizer.com

Abstract

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 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.

Ancillary