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

  • Luzelena CaroEmail author
  • Larissa Wenning
  • Hwa-Ping Feng
  • Zifang Guo
  • Lihong Du
  • Pratik Bhagunde
  • Christine Fandozzi
  • Deborah Panebianco
  • William L. Marshall
  • Joan R. Butterton
  • Marian Iwamoto
  • Wendy W. Yeh
Pharmacokinetics and Disposition
  • 35 Downloads

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

Hepatitis C Renal impairment Pharmacokinetics Haemodialysis 

Notes

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.

Author contributions

• 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

Source of Funding

This research was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Compliance with ethical standards

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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Copyright information

© Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA 2019

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Authors and Affiliations

  • Luzelena Caro
    • 1
    Email author
  • Larissa Wenning
    • 1
  • Hwa-Ping Feng
    • 1
  • Zifang Guo
    • 1
  • Lihong Du
    • 1
  • Pratik Bhagunde
    • 1
  • Christine Fandozzi
    • 1
  • Deborah Panebianco
    • 1
  • William L. Marshall
    • 1
  • Joan R. Butterton
    • 1
  • Marian Iwamoto
    • 1
  • Wendy W. Yeh
    • 1
  1. 1.Merck & Co., Inc.KenilworthUSA

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