Sofosbuvir and ribavirin exert their anti-hepatitis C virus (HCV) activity following metabolic activation in the liver. However, intrahepatic concentrations of the pharmacologically active nucleotide metabolites in humans are poorly characterized due to the inaccessibility of tissue and technical challenges with measuring nucleotide levels. A clinical study assessing the efficacy of sofosbuvir and ribavirin administered prior to liver transplant to prevent HCV reoccurrence provided a unique opportunity to quantify nucleotide concentrations in human liver. We analyzed nucleotides using high performance liquid chromatography coupled to tandem mass spectrometry in liver tissue from 30 HCV-infected patients with hepatocellular carcinoma who were administered sofosbuvir (400 mg/day) and ribavirin (1,000-1,200 mg/day) for between 3 and 52 weeks prior to liver transplantation. Median total hepatic metabolite concentrations (sum of nucleoside and mono-, di-, and tri-phosphates) were 77.1 μM for sofosbuvir and 361 μM for ribavirin in patients on therapy at the time of transplant. Ribavirin and sofosbuvir efficiently loaded the liver, with total hepatic concentrations exceeding maximal plasma levels by approximately 30-fold. Ribavirin metabolite levels suggest its monophosphate is in great excess of its inhibition constant for inosine monophosphate dehydrogenase and triphosphate is approaching the binding constant for incorporation by the HCV NS5B RNA-dependent RNA polymerase. Consistent with the potent antiviral activity of sofosbuvir, these results illustrate that liver triphosphate levels achieved following sofosbuvir administration greatly exceed the inhibition constant for HCV NS5B. In conclusion, this study expands the quantitative understanding of the pharmacology of sofosbuvir and ribavirin by establishing efficient hepatic delivery in the clinic.
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