Article date: November 2009
By: Jackson K. Mukonzo, Daniel Röshammar, Paul Waako, Maria Andersson, Takashi Fukasawa, Lili Milani, Jan Olof Svensson, Jasper Ogwal‐Okeng, Lars L. Gustafsson, Eleni Aklillu, in Volume 68, Issue 5, pages 690-699
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
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.
DOI: 10.1111/j.1365-2125.2009.03516.x
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