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

• Published in: European journal of clinical pharmacology Vol. 75; no. 5; pp. 665 - 675
• Main Authors: Caro, Luzelena, Wenning, Larissa, Feng, Hwa-Ping, Guo, Zifang, Du, Lihong, Bhagunde, Pratik, Fandozzi, Christine, Panebianco, Deborah, Marshall, William L., Butterton, Joan R., Iwamoto, Marian, Yeh, Wendy W.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.05.2019; Springer Nature B.V
• Subjects: Adult; Antiviral Agents - pharmacokinetics; Benzofurans - blood; Benzofurans - pharmacokinetics; Benzofurans - therapeutic use; Biomedical and Life Sciences; Biomedicine; Dosage; Drug Therapy, Combination; End-stage renal disease; Female; Hemodialysis; Hepacivirus - isolation & purification; Hepatitis C; Hepatitis C, Chronic - drug therapy; Hepatitis C, Chronic - physiopathology; Humans; Imidazoles - blood; Imidazoles - pharmacokinetics; Imidazoles - therapeutic use; Kidney diseases; Kidney Failure, Chronic - drug therapy; Kidney Failure, Chronic - therapy; Kidney Failure, Chronic - virology; Male; Medicare; Middle Aged; Pharmacokinetics; Pharmacokinetics and Disposition; Pharmacology/Toxicology; Quinoxalines - blood; Quinoxalines - pharmacokinetics; Quinoxalines - therapeutic use; Renal Dialysis; Renal impairment; Haemodialysis; Hepatitis C; Pharmacokinetics
• ISSN: 0031-6970; 1432-1041; 1432-1041
• DOI: 10.1007/s00228-018-2585-3

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 AUC 0–24 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 AUC 0–24 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 AUC 0–24 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 AUC 0–24 were 2.78 and 3.07 μM*h (HD and non-HD recipients) and GZR AUC 0–24 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.