Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil.
Coordenação de Pesquisa, Instituto Nacional de Câncer, Rio de Janeiro, Brazil.
Br J Clin Pharmacol. 2022 Oct;88(10):4585-4594. doi: 10.1111/bcp.15387. Epub 2022 May 25.
To investigate the influence of pharmacogenetic polymorphisms on efavirenz (EFV) exposure and metabolism in HIV-infected Brazilians under treatment with EFV-containing antiretroviral (ART) regimens.
HIV-positive adults (n = 82) on stable ART regimens containing 600 mg EFV once daily for at least 6 months were recruited at 2 university hospitals. Blood samples collected at mid-dose interval were used to quantify the plasma concentrations of EFV (denoted [EFV]), its major metabolite 8-OH-EFV ([8-OH-EFV]) and [8-OH-EFV]/[EFV] metabolic ratio, and to genotype single nucleotide polymorphisms in CYP2B6 (rs3745274, c.516G > T; rs28399499, c.983 T > C) and ABCB1 (rs3842, c.4036G > A). CYP2B6 metabolic phenotypes were inferred from the CYP2B6 diplotypes. Linear regression modelling was applied to identify sociodemographic, clinical and pharmacogenetic predictors of [EFV] and [8-OH-EFV]/[EFV] metabolic ratio.
Wide (50-fold) interindividual variation in [EFV], [8-OH-EFV] and [8-OH-EFV]/[EFV] was observed; 69.5% of participants had [EFV] within the nominal therapeutic range (1000-4000 ng/mL), while 19.5 and 11.0% had [EFV] below and above this range, respectively. Multiple regression modelling retained only CYP2B6 metabolic phenotypes or the combined rs3745274 and rs28399499 genotypes, as significant predictors of [EFV] and [8-OH-EFV]/[EFV].
EFV exposure and disposition varied widely among HIV-infected Brazilians under stable treatment with EFV-containing ART regimens. About 1/10 of the participants had [EFV] exceeding nominal supratherapeutic concentration (4000 ng/mL), but reported tolerance to the ARV regimens, while 1/5 of participants had nominal subtherapeutic [EFV] (<1000 ng/mL) but adequate virological response. Genotype for the 2 CYP2B6 single nucleotide polymorphisms studied explained 48% of variation in [EFV] and 35% of variation in [8-OH-EFV]/[EFV].
研究在接受含依非韦伦（EFV）的抗逆转录病毒（ART）治疗方案的巴西 HIV 感染者中，药物遗传学多态性对 EFV 暴露和代谢的影响。
在 2 所大学医院招募了 82 名接受至少 6 个月稳定的含 EFV（每日 600mg，1 次）ART 方案治疗的 HIV 阳性成人。在中剂量间隔采集血样，以定量检测 EFV（EFV）、其主要代谢物 8-羟基-EFV（8-OH-EFV）和 8-OH-EFV/EFV 代谢比的血浆浓度，并对 CYP2B6（rs3745274，c.516G>T；rs28399499，c.983T>C）和 ABCB1（rs3842，c.4036G>A）的单核苷酸多态性进行基因分型。CYP2B6 代谢表型是从 CYP2B6 二倍体推断出来的。线性回归模型用于确定 [EFV]和[8-OH-EFV]/EFV 代谢比的社会人口统计学、临床和药物遗传学预测因素。
观察到 [EFV]、[8-OH-EFV]和[8-OH-EFV]/EFV 个体间的差异很大（50 倍）；69.5%的参与者的[EFV]在名义治疗范围内（1000-4000ng/ml），而 19.5%和 11.0%的参与者的[EFV]分别低于和高于该范围。多元回归模型仅保留 CYP2B6 代谢表型或 rs3745274 和 rs28399499 基因型的组合，作为 [EFV]和[8-OH-EFV]/EFV 的显著预测因素。
在稳定接受含 EFV 的 ART 方案治疗的巴西 HIV 感染者中，EFV 的暴露和处置差异很大。约 1/10 的参与者的[EFV]超过了名义上的超治疗浓度（4000ng/ml），但对 ARV 方案耐受，而 1/5 的参与者的[EFV]低于名义上的治疗浓度（<1000ng/ml），但病毒学反应良好。研究的 2 个 CYP2B6 单核苷酸多态性的基因型解释了[EFV]变异的 48%和[8-OH-EFV]/EFV 变异的 35%。
