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 Citations (Scopus)

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)
JournalEuropean Journal of Clinical Pharmacology
DOIs
StateAccepted/In press - Jan 1 2018

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Pharmacokinetics
Safety
Liver
Area Under Curve
Protein Binding
Antiviral Agents
Headache
Blood Proteins

Keywords

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

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Pharmacokinetics and safety of glecaprevir and pibrentasvir in HCV-negative subjects with hepatic impairment. / Kosloski, Matthew P.; Wang, Haoyu; Pugatch, David; Mensa, Federico J.; Gane, Edward; Lawitz, Eric; Marbury, Thomas C.; Preston, Richard A; Kort, Jens; Liu, Wei.

In: European Journal of Clinical Pharmacology, 01.01.2018.

Research output: Contribution to journalArticle

Kosloski, Matthew P. ; Wang, Haoyu ; Pugatch, David ; Mensa, Federico J. ; Gane, Edward ; Lawitz, Eric ; Marbury, Thomas C. ; Preston, Richard A ; Kort, Jens ; Liu, Wei. / Pharmacokinetics and safety of glecaprevir and pibrentasvir in HCV-negative subjects with hepatic impairment. In: European Journal of Clinical Pharmacology. 2018.
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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.",
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T1 - Pharmacokinetics and safety of glecaprevir and pibrentasvir in HCV-negative subjects with hepatic impairment

AU - Kosloski, Matthew P.

AU - Wang, Haoyu

AU - Pugatch, David

AU - Mensa, Federico J.

AU - Gane, Edward

AU - Lawitz, Eric

AU - Marbury, Thomas C.

AU - Preston, Richard A

AU - Kort, Jens

AU - Liu, Wei

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

KW - Glecaprevir

KW - Hepatic impairment

KW - Hepatitis C virus

KW - Pharmacokinetics

KW - Pibrentasvir

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