Pharmacokinetics of elbasvir and grazoprevir in subjects with end-stage renal disease or severe renal impairment

Eur J Clin Pharmacol. 2019 May;75(5):665-675. doi: 10.1007/s00228-018-2585-3. Epub 2019 Jan 25.

Abstract

Purpose: To describe the phase 1 and population pharmacokinetic investigations that support dosing recommendations for elbasvir/grazoprevir (EBR/GZR) in hepatitis C virus-infected people with advanced chronic kidney disease.

Methods: This was an open-label, two-part, multiple-dose trial (MK-5172 PN050; NCT01937975) in 24 non-HCV-infected participants with end-stage renal disease (ESRD) or severe renal impairment who received once-daily EBR 50 mg and GZR 100 mg for 10 days. Population pharmacokinetic analyses from the phase 3 C-SURFER study (PN052, NCT02092350) were also conducted.

Results: When comparing haemodialysis (HD) and non-HD days in participants with ESRD, geometric mean ratios (GMRs) (90% confidence intervals [CIs]) for EBR and GZR AUC0-24 were 1.14 (1.08-1.21) and 0.97 (0.87-1.09). When comparing ESRD and healthy participants, GMRs (90% CIs) for EBR and GZR AUC0-24 were 0.99 (0.75-1.30) and 0.83 (0.56-1.22) on HD days, and 0.86 (0.65-1.14) and 0.85 (0.58-1.25) on non-HD days. GMRs (90% CIs) for AUC0-24 in participants with severe renal impairment relative to healthy controls were 1.65 (1.09-2.49) for GZR and 1.86 (1.38-2.51) for EBR. In population modelling of data from C-SURFER, absolute geometric means of steady-state EBR AUC0-24 were 2.78 and 3.07 μM*h (HD and non-HD recipients) and GZR AUC0-24 were 1.80 and 2.34 μM*h (HD and non-HD recipients).

Conclusions: EBR/GZR represents an important treatment option for HCV infection in people with severe renal impairment and those with ESRD. No dosage adjustment of EBR/GZR is required in people with any degree of renal impairment, including those receiving dialysis.

Keywords: Haemodialysis; Hepatitis C; Pharmacokinetics; Renal impairment.

Publication types

  • Clinical Trial, Phase I

MeSH terms

  • Adult
  • Amides
  • Antiviral Agents / pharmacokinetics*
  • Benzofurans / blood
  • Benzofurans / pharmacokinetics*
  • Benzofurans / therapeutic use
  • Carbamates
  • Cyclopropanes
  • Drug Therapy, Combination
  • Female
  • Hepacivirus / isolation & purification
  • Hepatitis C, Chronic / drug therapy
  • Hepatitis C, Chronic / physiopathology
  • Humans
  • Imidazoles / blood
  • Imidazoles / pharmacokinetics*
  • Imidazoles / therapeutic use
  • Kidney Failure, Chronic / drug therapy*
  • Kidney Failure, Chronic / therapy
  • Kidney Failure, Chronic / virology
  • Male
  • Middle Aged
  • Quinoxalines / blood
  • Quinoxalines / pharmacokinetics*
  • Quinoxalines / therapeutic use
  • Renal Dialysis
  • Sulfonamides

Substances

  • 2-(pyrrolidin-2-yl)-5-(2-(4-(5-(pyrrolidin-2-yl)-1H-imidazol-2-yl)phenyl)benzofuran-5-yl)-1H-imidazole
  • Amides
  • Antiviral Agents
  • Benzofurans
  • Carbamates
  • Cyclopropanes
  • Imidazoles
  • Quinoxalines
  • Sulfonamides
  • grazoprevir