A novel polymorphism in ABCB1 gene, CYP2B6*6 and sex predict single-dose efavirenz population pharmacokinetics in Ugandans.
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Date
2009
Journal Title
Journal ISSN
Volume Title
Publisher
British Journal of Clinical Pharmacology
Abstract
AIMS
Efavirenz exhibits pharmacokinetic variability causing varied clinical response. The aim
was to develop an integrated population pharmacokinetic/pharmacogenetic model and
investigate the impact of genetic variations, sex, demographic and biochemical variables on
single-dose efavirenz pharmacokinetics among Ugandan subjects, using NONMEM.
METHODS
Efavirenz plasma concentrations (n = 402) from 121 healthy subjects were quantified
by high-performance liquid chromatography. Subjects were genotyped for 30 single
nucleotide polymorphisms (SNPs), of which six were novel SNPs in CYP2B6, CYP3A5 and
ABCB1. The efavirenz pharmacokinetics was described by a two-compartment model with
zero- followed by first-order absorption.
RESULTS
Apparent oral clearance (95% confidence interval) was 4 l h l-1 (3.5, 4.5) in extensive
metabolizers. In the final model, incorporating multiple covariates, statistical significance
was found only for CYP2B6*6 and CYP2B6*11 on apparent oral clearance as well as ABCB1
(rs3842) on the relative bioavailability. Subjects homozygous for CYP2B6*6 (G516T, A785G)
and *11 displayed 21 and 20% lower apparent oral clearance, respectively. Efavirenz relative
bioavailability was 26% higher in subjects homozygous for ABCB1 (rs3842). The apparent
peripheral volume of distribution was twofold higher in women compared with men.
CONCLUSIONS
The model identified the four factors CYP2B6*6, CYP2B6*11, a novel variant allele in ABCB1
(rs3842) and sex as major predictors of efavirenz plasma exposure in a healthy Ugandan
population after single-dose administration. Use of mixed-effects modelling allowed the
analysis and integration of multiple pharmacogenetic and demographic covariates in a
pharmacokinetic population model.
Description
Keywords
ABCB1, CYP2B6, CYP3A5, efavirenz, Population pharmacokinetic, Ugandans
Citation
Mukonzo, J. K., Röshammar, D., Waako, P., Andersson, M., Fukasawa, T., Milani, L., ... & Aklillu, E. (2009). A novel polymorphism in ABCB1 gene, CYP2B6* 6 and sex predict single‐dose efavirenz population pharmacokinetics in Ugandans. British journal of clinical pharmacology, 68(5), 690-699.