Cusato Jessica, Boglione Lucio, De Nicolò Amedeo, Caviglia Gian Paolo, Mornese Pinna Simone, Ciancio Alessia, Troshina Giulia, Smedile Antonina, Antonucci Miriam, Avataneo Valeria, Palermiti Alice, Mula Jacopo, Manca Alessandra, Cariti Giuseppe, Cantù Marco, Saracco Giorgio Maria, Di Perri Giovanni, D'Avolio Antonio
Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, 10149 Turin, Italy.
Department of Traslational Medicine, University of Eastern Piedmont, 28100 Novara, Italy.
Pharmaceuticals (Basel). 2022 Mar 15;15(3):355. doi: 10.3390/ph15030355.
Sofosbuvir (SOF) is an HCV NS5B polymerase inhibitor, and GS-331007 is its major metabolite. The aim of this study was to investigate whether clinical and pharmacological factors could influence GS-331007 intracellular (IC) concentrations in peripheral blood mononuclear cells (PBMCs) associated with a sustained virological response in patients treated with SOF and ribavirin (RBV). Drug levels were analyzed using liquid chromatography at different days of therapy, whereas variants in genes encoding transporters and nuclear factors were investigated using real-time PCR. This study enrolled 245 patients treated with SOF; 245 samples were analyzed for pharmacogenetics and 50 were analyzed for IC pharmacokinetics. The GS-331007 IC concentration at 30 days was associated with its plasma concentration determinate at 30, 60 and 90 days of SOF-therapy and with daclatasvir concentrations at 7 days of therapy. No genetic polymorphism affected IC exposure. In linear multivariate analysis, ledipasvir treatment, baseline albumin and estimated glomerular filtration rate were significant predictors of IC exposure. This study presents data on an IC evaluation in a cohort of patients treated with SOF, also considering pharmacogenetics. These results could be useful for regions where SOF-RBV treatment is considered the standard of care; moreover, they could further deepen the knowledge of IC exposure for similar drugs in the future.
索磷布韦（SOF）是一种丙型肝炎病毒（HCV）NS5B聚合酶抑制剂，GS-331007是其主要代谢产物。本研究的目的是调查临床和药理学因素是否会影响在接受索磷布韦和利巴韦林（RBV）治疗的患者中与持续病毒学应答相关的外周血单核细胞（PBMC）内GS-331007的浓度。在治疗的不同天数使用液相色谱法分析药物水平，而使用实时聚合酶链反应研究编码转运蛋白和核因子的基因中的变体。本研究纳入了245例接受索磷布韦治疗的患者；对245份样本进行了药物遗传学分析，对50份样本进行了细胞内药代动力学分析。治疗30天时GS-331007的细胞内浓度与其在索磷布韦治疗30、60和90天时测定的血浆浓度以及治疗7天时的达卡他韦浓度相关。没有基因多态性影响细胞内暴露。在线性多变量分析中，来迪派韦治疗、基线白蛋白和估计肾小球滤过率是细胞内暴露的显著预测因素。本研究提供了一组接受索磷布韦治疗患者的细胞内评估数据，同时也考虑了药物遗传学。这些结果可能对将索磷布韦-利巴韦林治疗视为标准治疗方案的地区有用；此外，它们可能会在未来进一步加深对类似药物细胞内暴露的了解。
