Pharmacy Service, University Hospital of Salamanca, Salamanca, Spain.
Antimicrob Agents Chemother. 2011 Nov;55(11):5314-24. doi: 10.1128/AAC.00194-11. Epub 2011 Sep 6.
Despite extensive clinical experience with efavirenz (EFV), unpredictable interindividual variabilities in efficacy and toxicity remain important limitations associated with the use of this antiretroviral. The purpose of this study was to determine the factors affecting EFV pharmacokinetics and to develop a pharmacokinetic/pharmacogenetic (PK/PG) model in a Caucasian population of HIV-infected patients. In total, 869 EFV plasma concentrations from 128 HIV-infected patients treated with EFV were quantitatively assessed using a validated high-performance liquid chromatography technique. All patients were genotyped for 90 single nucleotide polymorphisms (SNPs) in genes coding for proteins involved in the metabolism and transport of EFV, using a MassArray platform provided by Sequenom. The influence of these polymorphisms on EFV pharmacokinetics and the effects of demographic, clinical, biochemical, lifestyle, and concurrent drug covariates were evaluated. Plasma concentrations were fitted by a one-compartment model, with first-order absorption and elimination using nonlinear mixed-effect modeling (NONMEM program). The CYP2B66 allele, multidrug resistance-associated protein 4 (MRP4) 1497C → T, and gamma-glutamyltranspeptidase (GGT) were identified as major factors influencing the apparent EFV oral clearance (CL/F), reducing the initial interindividual variability by 54.8%, according to the model CL/F = (12.2 - 0.00279 · GGT) · 0.602(CYP2B66 [G/T]) · 0.354(CYP2B66 [T/T]) · 0.793(MRP4 1497C → T), where CYP2B66 [G/T], CYP2B6*6 [T/T], and MRP4 1497C → T take values of 0 or 1 to indicate the absence or presence of polymorphisms. The detailed genetic analysis conducted in this study identified two of 90 SNPs that significantly impacted CL/F, which might indicate that the remaining SNPs analyzed do not influence this PK parameter, at least in Caucasian populations with characteristics similar to those of our study population.
尽管已广泛应用依非韦伦（EFV）治疗，但该药疗效和毒性仍存在个体间不可预测的变异性，这仍是应用该抗逆转录病毒药物的重要局限性。本研究旨在确定影响 EFV 药代动力学的因素，并在感染 HIV 的白种人群中建立药代动力学/遗传药理学（PK/PG）模型。共定量评估了 128 例接受 EFV 治疗的 HIV 感染患者的 869 次 EFV 血浆浓度，采用的方法是经验证的高效液相色谱技术。所有患者均采用Sequenom 公司提供的 MassArray 平台，对编码 EFV 代谢和转运蛋白的基因中的 90 个单核苷酸多态性（SNP）进行基因分型。评估了这些 SNP 对 EFV 药代动力学的影响，以及人口统计学、临床、生化、生活方式和同时使用的药物协变量的影响。采用非线性混合效应模型（NONMEM 程序）对一室模型进行拟合，模型包括一级吸收和消除。结果发现，CYP2B66 等位基因、多药耐药相关蛋白 4（MRP4）1497C→T 和谷氨酰转肽酶（GGT）是影响 EFV 表观口服清除率（CL/F）的主要因素，使初始个体间变异性降低了 54.8%，模型 CL/F =（12.2-0.00279·GGT）·0.602（CYP2B66[G/T]）·0.354（CYP2B66[T/T]）·0.793（MRP4 1497C→T），其中 CYP2B66[G/T]、CYP2B6*6[T/T]和 MRP4 1497C→T 的值为 0 或 1，以表示是否存在多态性。本研究进行的详细遗传分析确定了 90 个 SNP 中有两个显著影响 CL/F，这表明分析的其余 SNP 至少在与本研究人群特征相似的白种人群中不影响该 PK 参数。
