Institute of Microbiology, University Hospital Center, University of Lausanne, Lausanne, Switzerland.
Pharmacogenet Genomics. 2013 Jan;23(1):9-18. doi: 10.1097/FPC.0b013e32835ade82.
Etravirine (ETV) is metabolized by cytochrome P450 (CYP) 3A, 2C9, and 2C19. Metabolites are glucuronidated by uridine diphosphate glucuronosyltransferases (UGT). To identify the potential impact of genetic and non-genetic factors involved in ETV metabolism, we carried out a two-step pharmacogenetics-based population pharmacokinetic study in HIV-1 infected individuals.
The study population included 144 individuals contributing 289 ETV plasma concentrations and four individuals contributing 23 ETV plasma concentrations collected in a rich sampling design. Genetic variants [n=125 single-nucleotide polymorphisms (SNPs)] in 34 genes with a predicted role in ETV metabolism were selected. A first step population pharmacokinetic model included non-genetic and known genetic factors (seven SNPs in CYP2C, one SNP in CYP3A5) as covariates. Post-hoc individual ETV clearance (CL) was used in a second (discovery) step, in which the effect of the remaining 98 SNPs in CYP3A, P450 cytochrome oxidoreductase (POR), nuclear receptor genes, and UGTs was investigated.
A one-compartment model with zero-order absorption best characterized ETV pharmacokinetics. The average ETV CL was 41 (l/h) (CV 51.1%), the volume of distribution was 1325 l, and the mean absorption time was 1.2 h. The administration of darunavir/ritonavir or tenofovir was the only non-genetic covariate influencing ETV CL significantly, resulting in a 40% [95% confidence interval (CI): 13-69%] and a 42% (95% CI: 17-68%) increase in ETV CL, respectively. Carriers of rs4244285 (CYP2C19*2) had 23% (8-38%) lower ETV CL. Co-administered antiretroviral agents and genetic factors explained 16% of the variance in ETV concentrations. None of the SNPs in the discovery step influenced ETV CL.
ETV concentrations are highly variable, and co-administered antiretroviral agents and genetic factors explained only a modest part of the interindividual variability in ETV elimination. Opposing effects of interacting drugs effectively abrogate genetic influences on ETV CL, and vice-versa.
依曲韦林（ETV）由细胞色素 P450（CYP）3A、2C9 和 2C19 代谢，代谢物由尿苷二磷酸葡萄糖醛酸基转移酶（UGT）葡萄糖醛酸化。为了确定与 ETV 代谢相关的遗传和非遗传因素的潜在影响，我们对 HIV-1 感染者进行了两步基于药物遗传学的群体药代动力学研究。
研究人群包括 144 名个体，共提供了 289 个 ETV 血浆浓度，4 名个体共提供了 23 个 ETV 血浆浓度，采用了丰富的采样设计进行采集。选择了 34 个具有预测 ETV 代谢作用的基因中的 125 个单核苷酸多态性（SNP）。第一个群体药代动力学模型包括非遗传和已知遗传因素（CYP2C 中的 7 个 SNP，CYP3A5 中的 1 个 SNP）作为协变量。个体 ETV 清除率（CL）用于第二步（发现），其中研究了 CYP3A、细胞色素 P450 氧化还原酶（POR）、核受体基因和 UGT 中剩余的 98 个 SNP 的作用。
零级吸收的单室模型最好地描述了 ETV 药代动力学。ETV 的平均 CL 为 41（l/h）（CV 51.1%），分布容积为 1325 l，平均吸收时间为 1.2 h。达鲁那韦/利托那韦或替诺福韦的给药是非遗传协变量，显著影响 ETV CL，分别导致 ETV CL 增加 40%（95%CI：13-69%）和 42%（95%CI：17-68%）。CYP2C19*2 携带者的 ETV CL 降低了 23%（8-38%）。同时使用的抗逆转录病毒药物和遗传因素解释了 ETV 浓度的 16%的方差。发现步骤中的 SNP 均未影响 ETV CL。
ETV 浓度高度可变，同时使用的抗逆转录病毒药物和遗传因素仅能部分解释 ETV 消除的个体间变异性。相互作用药物的相反作用有效地消除了遗传对 ETV CL 的影响，反之亦然。
