Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska University Hospital-Huddinge, Karolinska Institutet, Stockholm, Sweden.
Br J Clin Pharmacol. 2009 Nov;68(5):690-9. doi: 10.1111/j.1365-2125.2009.03516.x.
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.
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.
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 CYP2B66 and CYP2B611 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.
The model identified the four factors CYP2B66, CYP2B611, 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.
依非韦伦表现出的药代动力学变异性导致了不同的临床反应。本研究旨在建立一个整合的群体药代动力学/遗传药理学模型，并使用 NONMEM 方法，调查遗传变异、性别、人口统计学和生化变量对乌干达受试者单次给予依非韦伦后的药代动力学的影响。
采用高效液相色谱法对 121 例健康受试者的依非韦伦血浆浓度（n = 402）进行定量分析。对受试者的 30 个单核苷酸多态性（SNP）进行基因分型，其中 CYP2B6、CYP3A5 和 ABCB1 中的 6 个是新的 SNP。依非韦伦药代动力学采用二室模型描述，零级吸收后接着是一级吸收。
在广泛代谢者中，表观口服清除率（95%置信区间）为 4 l h l(-1)（3.5，4.5）。在最终模型中，纳入多个协变量后，只有 CYP2B66 和 CYP2B611 对表观口服清除率以及 ABCB1（rs3842）对相对生物利用度有统计学意义。CYP2B66（G516T，A785G）和11 的纯合子受试者的表观口服清除率分别降低了 21%和 20%。ABCB1（rs3842）的纯合子受试者的依非韦伦相对生物利用度增加了 26%。与男性相比，女性的表观外周分布容积增加了一倍。
该模型确定了 CYP2B66、CYP2B611、ABCB1（rs3842）的新变异等位基因和性别是乌干达健康人群单次给予依非韦伦后影响依非韦伦血浆暴露的主要预测因素。混合效应模型的使用允许在群体药代动力学模型中分析和整合多个遗传和人口统计学协变量。
