Arab-Alameddine M, Di Iulio J, Buclin T, Rotger M, Lubomirov R, Cavassini M, Fayet A, Décosterd L A, Eap C B, Biollaz J, Telenti A, Csajka C
Division of Clinical Pharmacology and Toxicology, University Hospital Center, University of Lausanne, Lausanne, Switzerland.
Clin Pharmacol Ther. 2009 May;85(5):485-94. doi: 10.1038/clpt.2008.271. Epub 2009 Feb 18.
Besides CYP2B6, other polymorphic enzymes contribute to efavirenz (EFV) interindividual variability. This study was aimed at quantifying the impact of multiple alleles on EFV disposition. Plasma samples from 169 human immunodeficiency virus (HIV) patients characterized for CYP2B6, CYP2A6, and CYP3A4/5 allelic diversity were used to build up a population pharmacokinetic model using NONMEM (non-linear mixed effects modeling), the aim being to seek a general approach combining genetic and demographic covariates. Average clearance (CL) was 11.3 l/h with a 65% interindividual variability that was explained largely by CYP2B6 genetic variation (31%). CYP2A6 and CYP3A4 had a prominent influence on CL, mostly when CYP2B6 was impaired. Pharmacogenetics fully accounted for ethnicity, leaving body weight as the only significant demographic factor influencing CL. Square roots of the numbers of functional alleles best described the influence of each gene, without interaction. Functional genetic variations in both principal and accessory metabolic pathways demonstrate a joint impact on EFV disposition. Therefore, dosage adjustment in accordance with the type of polymorphism (CYP2B6, CYP2A6, or CYP3A4) is required in order to maintain EFV within the therapeutic target levels.
除CYP2B6外，其他多态性酶也导致了依非韦伦（EFV）个体间的差异。本研究旨在量化多个等位基因对EFV处置的影响。利用来自169例以CYP2B6、CYP2A6和CYP3A4/5等位基因多样性为特征的人类免疫缺陷病毒（HIV）患者的血浆样本，采用NONMEM（非线性混合效应模型）建立群体药代动力学模型，目的是寻求一种结合遗传和人口统计学协变量的通用方法。平均清除率（CL）为11.3 l/h，个体间差异为65%，这在很大程度上由CYP2B6基因变异所解释（31%）。CYP2A6和CYP3A4对CL有显著影响，主要是在CYP2B6功能受损时。药物遗传学完全解释了种族因素，体重是影响CL的唯一显著人口统计学因素。功能等位基因数量的平方根最能描述每个基因的影响，且不存在相互作用。主要和辅助代谢途径中的功能性基因变异均对EFV处置有联合影响。因此，为了将EFV维持在治疗目标水平，需要根据多态性类型（CYP2B6、CYP2A6或CYP3A4）进行剂量调整。
