Pharmacokinetics and safety of glecaprevir and pibrentasvir in HCV-negative subjects with hepatic impairment

Matthew P. Kosloski, Haoyu Wang, David Pugatch, Federico J. Mensa, Edward Gane, Eric Lawitz, Thomas C. Marbury, Richard A. Preston, Jens Kort, Wei Liu

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Purpose: This study characterized the effects of hepatic impairment on the pharmacokinetics and safety of glecaprevir and pibrentasvir, two direct-acting antivirals used for treatment of chronic HCV infection. Methods: HCV-negative subjects with normal hepatic function, or with mild (Child-Pugh [CP]-A), moderate (CP-B), or severe (CP-C) hepatic impairment received single doses of pibrentasvir 120 mg alone or with glecaprevir 200 mg or 300 mg (n = 6/functional group/dose). Plasma pharmacokinetics and protein binding were evaluated. Doses were separated by ≥ 14 days of washout. Results: For the approved combination of glecaprevir 300 mg with pibrentasvir 120 mg, glecaprevir AUC was increased by 33% (CP-A), to 2.0-fold (CP-B), and to 11-fold (CP-C) relative to normal subjects; pibrentasvir AUC was ≤ 26% different (CP-A or CP-B) and increased to 2.1-fold (CP-C). For glecaprevir 200 mg with pibrentasvir 120 mg, glecaprevir AUC was increased by 80% (CP-A) or to 2.8-fold (CP-B), while pibrentasvir AUC was unaffected in the same subjects (≤ 12% difference). Pibrentasvir 120 mg alone AUC increased 51% (CP-A), 31% (CP-B), and to 5.2-fold (CP-C). The unbound fraction of glecaprevir was higher in CP-C subjects than normal subjects and pibrentasvir protein binding was similar across groups. The most common adverse event was headache; no events were serious. Conclusion: This study supported evaluation of the glecaprevir 300 mg with pibrentasvir 120-mg combination in HCV-infected subjects with CP-A hepatic impairment without dose adjustment. Elevated glecaprevir and/or pibrentasvir exposures are expected in HCV-infected patients with CP-B or CP-C hepatic impairment.

Original languageEnglish (US)
Pages (from-to)217-226
Number of pages10
JournalEuropean Journal of Clinical Pharmacology
Volume75
Issue number2
DOIs
StatePublished - Feb 6 2019

Keywords

  • Glecaprevir
  • Hepatic impairment
  • Hepatitis C virus
  • Pharmacokinetics
  • Pibrentasvir

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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    Kosloski, M. P., Wang, H., Pugatch, D., Mensa, F. J., Gane, E., Lawitz, E., Marbury, T. C., Preston, R. A., Kort, J., & Liu, W. (2019). Pharmacokinetics and safety of glecaprevir and pibrentasvir in HCV-negative subjects with hepatic impairment. European Journal of Clinical Pharmacology, 75(2), 217-226. https://doi.org/10.1007/s00228-018-2576-4