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

Abstract

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.

Keywords: ABCB1; ABCG2; DAAs; HNF4α; pharmacokinetics; single nucleotide polymorphism.

Figure 1

GS-331007 intracellular levels at 30 days of therapy correlated with sofosbuvir plasma concentrations at 30 days (A), at 60 days (B), at 90 days (C) and with daclatasvir (DAC) plasma concentrations at 7 days (D). p = p-value, P = Pearson coefficient.

Figure 2

GS-331007 IC levels at 30 days of therapy correlated with baseline estimated glomerular filtration rate in all patients (p-value = 0.036 and Pearson coefficient = −0.291).

Figure 3

GS-331007 IC levels at 30 days of therapy correlated with the baseline estimated glomerular filtration rate cutoff value of 60 mL/min (p-value = 0.018, N = 48 for >60 mL/min; N = 2 for <60 mL/min).

Figure 4

GS-331007 plasma levels at 30 days of therapy correlated with the baseline estimated glomerular filtration rate cutoff value of 60 mL/min (p-value = 0.032; N = 48 for >60 mL/min; N = 2 for < 60 mL/min).