Effect of hepatic impairment on the pharmacokinetics of grazoprevir, a hepatitis C virus protease inhibitor

Luzelena Caro, Larissa Wenning, Zifang Guo, Iain P. Fraser, Christine Fandozzi, Jennifer Talaty, Deborah Panebianco, Maureen Ho, Naoto Uemura, Christina Reitmann, Peter Angus, Edward Gane, Thomas Marbury, William Smith, Marian Iwamoto, Joan R. Butterton, Wendy W. Yeh

Research output: Contribution to journalArticle

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Abstract

Grazoprevir (GZR) plus elbasvir is an approved treatment for chronic infection with hepatitis C virus (HCV) genotype 1 or 4. HCV infection complications include liver cirrhosis, end-stage liver disease, and hepatocellular carcinoma. The objective of this study was to evaluate the pharmacokinetics and safety of multiple-dose GZR (200, 100, or 50 mg) in non-HCV participants with mild, moderate, or severe hepatic impairment (HI), respectively, and in healthy matched controls (protocol MK-5172_p013; Merck & Co., Inc., Kenilworth, NJ). Participants with mild, moderate, or severe HI and controls (aged 18 to 65 years) matched for race, age, sex, and body mass index were enrolled in a 3-part, open-label, sequential-panel pharmacokinetic study. Participants received oral doses of GZR 200 mg (two 100-mg tablets), 100 mg (one 100-mg tablet), or 50 mg (two 25-mg tablets) once daily for 10 days. A total of 50 participants were enrolled: 8 with mild HI, 9 with moderate HI, 8 with severe HI, and a corresponding number of healthy matched controls for each hepatic cohort. Participants with HI demonstrated higher GZR exposure than healthy matched controls and showed an increase in exposure with increasing HI severity. The steady-state GZR AUC0–24 (area under the concentration-time curve from 0 to 24 h) for participants with mild, moderate, or severe HI was ≈2-, ≈5-, or ≈12-fold higher, respectively, than that for healthy matched controls. GZR was generally well tolerated in participants with HI. No dose adjustment is required for GZR in people with HCV with mild HI. GZR is contraindicated for those with moderate or severe HI (Child-Pugh class B or C), since they may have significantly increased GZR exposures that may lead to an increased risk of transaminase elevation.

Original languageEnglish (US)
Article numbere00813
JournalAntimicrobial Agents and Chemotherapy
Volume61
Issue number12
DOIs
StatePublished - Dec 1 2017

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Protease Inhibitors
Hepacivirus
Pharmacokinetics
Liver
Tablets
MK-5172
End Stage Liver Disease
Virus Diseases
Transaminases
Liver Cirrhosis
Hepatocellular Carcinoma
Body Mass Index
Genotype
Viruses
Safety

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Effect of hepatic impairment on the pharmacokinetics of grazoprevir, a hepatitis C virus protease inhibitor. / Caro, Luzelena; Wenning, Larissa; Guo, Zifang; Fraser, Iain P.; Fandozzi, Christine; Talaty, Jennifer; Panebianco, Deborah; Ho, Maureen; Uemura, Naoto; Reitmann, Christina; Angus, Peter; Gane, Edward; Marbury, Thomas; Smith, William; Iwamoto, Marian; Butterton, Joan R.; Yeh, Wendy W.

In: Antimicrobial Agents and Chemotherapy, Vol. 61, No. 12, e00813, 01.12.2017.

Research output: Contribution to journalArticle

Caro, L, Wenning, L, Guo, Z, Fraser, IP, Fandozzi, C, Talaty, J, Panebianco, D, Ho, M, Uemura, N, Reitmann, C, Angus, P, Gane, E, Marbury, T, Smith, W, Iwamoto, M, Butterton, JR & Yeh, WW 2017, 'Effect of hepatic impairment on the pharmacokinetics of grazoprevir, a hepatitis C virus protease inhibitor', Antimicrobial Agents and Chemotherapy, vol. 61, no. 12, e00813. https://doi.org/10.1128/AAC.00813-17
Caro, Luzelena ; Wenning, Larissa ; Guo, Zifang ; Fraser, Iain P. ; Fandozzi, Christine ; Talaty, Jennifer ; Panebianco, Deborah ; Ho, Maureen ; Uemura, Naoto ; Reitmann, Christina ; Angus, Peter ; Gane, Edward ; Marbury, Thomas ; Smith, William ; Iwamoto, Marian ; Butterton, Joan R. ; Yeh, Wendy W. / Effect of hepatic impairment on the pharmacokinetics of grazoprevir, a hepatitis C virus protease inhibitor. In: Antimicrobial Agents and Chemotherapy. 2017 ; Vol. 61, No. 12.
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abstract = "Grazoprevir (GZR) plus elbasvir is an approved treatment for chronic infection with hepatitis C virus (HCV) genotype 1 or 4. HCV infection complications include liver cirrhosis, end-stage liver disease, and hepatocellular carcinoma. The objective of this study was to evaluate the pharmacokinetics and safety of multiple-dose GZR (200, 100, or 50 mg) in non-HCV participants with mild, moderate, or severe hepatic impairment (HI), respectively, and in healthy matched controls (protocol MK-5172_p013; Merck & Co., Inc., Kenilworth, NJ). Participants with mild, moderate, or severe HI and controls (aged 18 to 65 years) matched for race, age, sex, and body mass index were enrolled in a 3-part, open-label, sequential-panel pharmacokinetic study. Participants received oral doses of GZR 200 mg (two 100-mg tablets), 100 mg (one 100-mg tablet), or 50 mg (two 25-mg tablets) once daily for 10 days. A total of 50 participants were enrolled: 8 with mild HI, 9 with moderate HI, 8 with severe HI, and a corresponding number of healthy matched controls for each hepatic cohort. Participants with HI demonstrated higher GZR exposure than healthy matched controls and showed an increase in exposure with increasing HI severity. The steady-state GZR AUC0–24 (area under the concentration-time curve from 0 to 24 h) for participants with mild, moderate, or severe HI was ≈2-, ≈5-, or ≈12-fold higher, respectively, than that for healthy matched controls. GZR was generally well tolerated in participants with HI. No dose adjustment is required for GZR in people with HCV with mild HI. GZR is contraindicated for those with moderate or severe HI (Child-Pugh class B or C), since they may have significantly increased GZR exposures that may lead to an increased risk of transaminase elevation.",
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AU - Fandozzi, Christine

AU - Talaty, Jennifer

AU - Panebianco, Deborah

AU - Ho, Maureen

AU - Uemura, Naoto

AU - Reitmann, Christina

AU - Angus, Peter

AU - Gane, Edward

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