Factors Influencing the Intracellular Concentrations of the Sofosbuvir Metabolite GS-331007 (in PBMCs) at 30 Days of Therapy

被引:1
|
作者
Cusato, Jessica [1 ]
Boglione, Lucio [2 ]
De Nicolo, Amedeo [1 ]
Caviglia, Gian Paolo [1 ]
Pinna, Simone Mornese [1 ]
Ciancio, Alessia [1 ]
Troshina, Giulia [1 ]
Smedile, Antonina [1 ]
Antonucci, Miriam [1 ]
Avataneo, Valeria [1 ]
Palermiti, Alice [1 ]
Mula, Jacopo [1 ]
Manca, Alessandra [1 ]
Cariti, Giuseppe [1 ]
Cantu, Marco [3 ]
Saracco, Giorgio Maria [1 ]
Di Perri, Giovanni [1 ]
D'Avolio, Antonio [1 ,4 ]
机构
[1] Univ Turin, Amedeo di Savoia Hosp, Dept Med Sci, I-10149 Turin, Italy
[2] Univ Piemonte Orientale, Dept Traslat Med, I-28100 Novara, Italy
[3] Ente Osped Cantonale, Lab Clin Biochem & Pharmacol, Dept Lab Med EOLAB, CH-6500 Bellinzona, Switzerland
[4] Univ Turin, Interdept Ctr Clin & Expt Pharmacol CIFACS, I-10149 Turin, Italy
关键词
DAAs; single nucleotide polymorphism; pharmacokinetics; ABCB1; ABCG2; HNF4; alpha; C VIRUS-INFECTION; UPLC-MS/MS METHOD; HEPATITIS-C; ANTIVIRAL THERAPY; DRUG TRANSPORTERS; HCV PATIENTS; PHARMACOKINETICS; QUANTIFICATION; GENOTYPE; PHARMACODYNAMICS;
D O I
10.3390/ph15030355
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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.
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页数:12
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