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European Journal of Clinical Pharmacology

, Volume 75, Issue 2, pp 217–226 | Cite as

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 LiuEmail author
Pharmacokinetics and Disposition

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.

Keywords

Glecaprevir Pibrentasvir Pharmacokinetics Hepatitis C virus Hepatic impairment 

Notes

Acknowledgements

The authors thank AbbVie employee Sonja Causemaker for medical writing support of this manuscript.

Authors’ contributions

MPK, HW, DP, FJM, EG, EL, TCM, RAP, JK, and WL contributed to the study design and analysis and interpretation of the data as well as the drafting and revising of the manuscript.

Funding

This study was funded by AbbVie. AbbVie participated in the design, study conduct, analysis, and interpretation of data as well as the writing, review, and approval of the manuscript.

Compliance with ethical standards

Conflict of interest

Matthew Kosloski, Haoyu Wang, David Pugatch, Federico Mensa, Jens Kort, and Wei Liu are employees of AbbVie, Inc. and may hold stock or stock options. Edward Gane is faculty at University of Auckland, Auckland, New Zealand, is a consultant/Advisory Board member for AbbVie, Gilead, Janssen, and Merck/MSD, and is a speaker for AbbVie and Gilead. Eric Lawitz is an employee of Texas Liver Institute, University of Texas Health San Antonio, San Antonio, TX, USA and is a speaker for AbbVie, Gilead, and Merck. Dr. Lawitz has received research/grant support from AbbVie, Boehringer Ingelheim, BMS, Gilead Sciences, GSK, Intercept Pharmaceuticals, Janssen, Merck, and Novartis, and he serves as an advisor for AbbVie, Achillion, BioCryst, Biotica, Enanta, Janssen, Merck, and Novartis. Thomas C. Marbury is an employee and equity owner of Orlando Clinical Research Center, Orlando, FL, USA and has no other conflicts of interest to disclose. Richard A. Preston is faculty at the Miller School of Medicine, University of Miami, Miami, FL, USA and he has received grant/research support from AbbVie, Celerion, Chiasma, Celgene, Conatus, Forest, Pfizer, Parexel, PPD, Takeda, Novartis, Exelixis, Idenix, PPD, Akros, ApoPharma, Merck, Fujifi lm, Reata, and Watson.

Ethical approval

The study was conducted in accordance with International Conference for Harmonization Good Clinical Practice guidelines and ethical principles that have their origin in the Declaration of Helsinki.

Informed consent

Written informed consent was obtained from each subject before any study-related procedures were performed.

Supplementary material

228_2018_2576_MOESM1_ESM.docx (17 kb)
ESM 1 (DOCX 17 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Matthew P. Kosloski
    • 1
  • Haoyu Wang
    • 2
  • David Pugatch
    • 3
  • Federico J. Mensa
    • 3
  • Edward Gane
    • 4
  • Eric Lawitz
    • 5
  • Thomas C. Marbury
    • 6
  • Richard A. Preston
    • 7
    • 8
  • Jens Kort
    • 9
  • Wei Liu
    • 1
    Email author
  1. 1.Clinical Pharmacology and Pharmacometrics, AbbVie Inc.North ChicagoUSA
  2. 2.Data and Statistical Sciences, AbbVie Inc.North ChicagoUSA
  3. 3.Infectious Diseases, AbbVie Inc.North ChicagoUSA
  4. 4.University of AucklandAucklandNew Zealand
  5. 5.Texas Liver InstituteUniversity of Texas HealthSan AntonioUSA
  6. 6.Orlando Clinical Research CenterOrlandoUSA
  7. 7.Division of Clinical Pharmacology, Department of Medicine, Miller School of MedicineUniversity of MiamiMiamiUSA
  8. 8.Department of Cellular Biology and Pharmacology, Herbert Wertheim College of MedicineFlorida International UniversityMiamiUSA
  9. 9.Medical Affairs, AbbVie Inc.North ChicagoUSA

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