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.
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Acknowledgments
We thank all the participants and clinical research unit staff who participated in these trials. Medical writing and editorial assistance was provided by Tim Ibbotson, PhD, of ApotheCom (Yardley, PA) and funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Funding
This research was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
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• Conceived of or designed study: LC, JRB, MI, WWY
• Performed research: LC, LW, DP, CF, WLM, JRB, WWY
• Analysed data: All authors
• Wrote the paper: LC, LW, H-PF, WWY
• Revised manuscript or reviewed it for important intellectual content: All authors
• Read and approved the final version for submission: All authors
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Conflict of interest
LC, LW, H-PF, ZG, LD, PB, CF, DP, JRB, MI, and WWY are current employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (MSD) and may hold stock in Merck & Co., Inc., Kenilworth, NJ, USA. WLM was an employee of MSD at the time the study was conducted.
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Caro, L., Wenning, L., Feng, HP. et al. Pharmacokinetics of elbasvir and grazoprevir in subjects with end-stage renal disease or severe renal impairment. Eur J Clin Pharmacol 75, 665–675 (2019). https://doi.org/10.1007/s00228-018-2585-3
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DOI: https://doi.org/10.1007/s00228-018-2585-3