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Pharmacokinetics, Efficacy, and Safety of Hepatitis C Virus Drugs in Patients with Liver and/or Renal Impairment.

ABSTRACT: Hepatitis C virus (HCV)-infected patients often suffer from liver cirrhosis, which can be complicated by renal impairment. Therefore, in this review we describe the treatment possibilities in HCV patients with hepatic and renal impairment. Cirrhosis alters the structure of the liver, which affects drug-metabolizing enzymes and drug transporters. These modifications influence the plasma concentration of substrates of drugs metabolized/transported by these enzymes. The direct-acting antivirals (DAAs) are substrates of, for example, cytochrome P450 enzymes in the liver. Most DAAs are not studied in HCV-infected individuals with decompensated cirrhosis, and therefore awareness is needed when these patients are treated. Most DAAs are contraindicated in cirrhotic patients; however, patients with a Child-Pugh score of B or C can be treated safely with a normal dose sofosbuvir plus ledipasvir or daclatasvir, in combination with ribavirin. Patients with renal impairment (glomerular filtration rate [GFR] <90 mL/min) or who are dependent on dialysis often tolerate ribavirin treatment poorly, even after dose adjustments. However, most DAAs can be used at the normal dose because DAAs are not renally excreted. To date, grazoprevir plus elbasvir is the preferred DAA regimen in patients with renal impairment as data are pending for sofosbuvir patients with GFR <30 mL/min (as for ledipasvir and velpatasvir). However, sofosbuvir has been used in a small number of patients with severe renal impairment and, based on these trials, we recommend sofosbuvir 400 mg every day when no other DAA regimen is available. Ledipasvir and velpatasvir are not recommended in patients with severe renal impairment.

SUBMITTER: Smolders EJ

PROVIDER: S-EPMC4912979 | biostudies-other | 2016 Jul

REPOSITORIES: biostudies-other

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Pharmacokinetics, Efficacy, and Safety of Hepatitis C Virus Drugs in Patients with Liver and/or Renal Impairment.

Smolders Elise J EJ de Kanter Clara T M M CT van Hoek Bart B Arends Joop E JE Drenth Joost P H JP Burger David M DM

Drug safety 20160701 7

Hepatitis C virus (HCV)-infected patients often suffer from liver cirrhosis, which can be complicated by renal impairment. Therefore, in this review we describe the treatment possibilities in HCV patients with hepatic and renal impairment. Cirrhosis alters the structure of the liver, which affects drug-metabolizing enzymes and drug transporters. These modifications influence the plasma concentration of substrates of drugs metabolized/transported by these enzymes. The direct-acting antivirals (DA ...[more]

PMID: 27098247

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Project description:Sofosbuvir and ribavirin exert their anti-hepatitis C virus (anti-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 transplantation to prevent HCV recurrence 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 to 1,200 mg/day) for 3 to 52 weeks prior to liver transplantation. Median total hepatic metabolite concentrations (the sum of nucleoside and mono-, di-, and triphosphates) were 77.1 ?M for sofosbuvir and 361 ?M for ribavirin in patients on therapy at the time of transplantation. Ribavirin and sofosbuvir efficiently loaded the liver, with total hepatic metabolite concentrations exceeding maximal levels in plasma by approximately 30-fold. Ribavirin metabolite levels suggest that its monophosphate is in great excess of its inhibition constant for IMP dehydrogenase and that its triphosphate is approaching the binding constant for incorporation by the HCV NS5B RNA-dependent RNA polymerase. In accordance with the potent antiviral activity of sofosbuvir, these results demonstrate that the 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. (This study has been registered at ClinicalTrials.gov under identifier NCT01559844.).

Dataset Information

Pharmacokinetics, Efficacy, and Safety of Hepatitis C Virus Drugs in Patients with Liver and/or Renal Impairment.

Publications

Pharmacokinetics, Efficacy, and Safety of Hepatitis C Virus Drugs in Patients with Liver and/or Renal Impairment.

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