Pharmacokinetics, Safety, and Tolerability of Single-Dose Elbasvir in Participants with Hepatic Impairment

William L. Marshall, Hwa Ping Feng, Larissa Wenning, Graigory Garrett, Xiaobi Huang, Fang Liu, Deborah Panebianco, Luzelena Caro, Christine Fandozzi, Kenneth C. Lasseter, Richard A Preston, Thomas Marbury, Joan R. Butterton, Marian Iwamoto, Wendy W. Yeh

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Background: The combination of elbasvir and grazoprevir is approved for the treatment of hepatitis C virus genotype 1 or 4 infection. Objective: To evaluate the pharmacokinetics and safety of single-dose elbasvir 50 mg in participants with hepatic impairment. Methods: Participants with mild, moderate, or severe hepatic impairment and age-, sex-, and weight-matched healthy controls were enrolled in a 3-part, open-label, sequential-panel, single-dose pharmacokinetic study. Blood samples were collected to assess pharmacokinetics. Safety and tolerability were assessed throughout the study. Results: Thirty-four participants were enrolled: eight with mild hepatic impairment, 11 with moderate hepatic impairment, seven with severe hepatic impairment, and eight healthy matched controls. Participants with mild, moderate, and severe hepatic impairment demonstrated a numeric, but not statistically significant, decrease in elbasvir exposure compared with controls, with a mean 39, 28, and 12% decrease in area under the concentration–time curve from time 0 extrapolated to infinity, as well as a 42, 31, and 42% decrease in maximum plasma concentration (Cmax), respectively. The observed median time to Cmax was similar in participants with hepatic impairment and controls. Single-dose administration of elbasvir was well tolerated. Conclusions: The pharmacokinetics of elbasvir after a single, oral 50-mg dose were not clinically meaningfully altered in non–HCV-infected participants with mild, moderate, or severe hepatic dysfunction. However, since elbasvir is currently available only as part of a fixed-dose combination with grazoprevir, the fixed-dose combination should not be administered to patients with moderate or severe hepatic impairment, due to the significantly increased plasma grazoprevir exposures in those populations.

Original languageEnglish (US)
Pages (from-to)1-9
Number of pages9
JournalEuropean Journal of Drug Metabolism and Pharmacokinetics
DOIs
StateAccepted/In press - Dec 15 2017
Externally publishedYes

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Pharmacokinetics
Safety
Liver
2-(pyrrolidin-2-yl)-5-(2-(4-(5-(pyrrolidin-2-yl)-1H-imidazol-2-yl)phenyl)benzofuran-5-yl)-1H-imidazole
Hepacivirus
Area Under Curve
Genotype
Weights and Measures
Infection
Population
MK-5172

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Pharmacokinetics, Safety, and Tolerability of Single-Dose Elbasvir in Participants with Hepatic Impairment. / Marshall, William L.; Feng, Hwa Ping; Wenning, Larissa; Garrett, Graigory; Huang, Xiaobi; Liu, Fang; Panebianco, Deborah; Caro, Luzelena; Fandozzi, Christine; Lasseter, Kenneth C.; Preston, Richard A; Marbury, Thomas; Butterton, Joan R.; Iwamoto, Marian; Yeh, Wendy W.

In: European Journal of Drug Metabolism and Pharmacokinetics, 15.12.2017, p. 1-9.

Research output: Contribution to journalArticle

Marshall, WL, Feng, HP, Wenning, L, Garrett, G, Huang, X, Liu, F, Panebianco, D, Caro, L, Fandozzi, C, Lasseter, KC, Preston, RA, Marbury, T, Butterton, JR, Iwamoto, M & Yeh, WW 2017, 'Pharmacokinetics, Safety, and Tolerability of Single-Dose Elbasvir in Participants with Hepatic Impairment', European Journal of Drug Metabolism and Pharmacokinetics, pp. 1-9. https://doi.org/10.1007/s13318-017-0451-9
Marshall, William L. ; Feng, Hwa Ping ; Wenning, Larissa ; Garrett, Graigory ; Huang, Xiaobi ; Liu, Fang ; Panebianco, Deborah ; Caro, Luzelena ; Fandozzi, Christine ; Lasseter, Kenneth C. ; Preston, Richard A ; Marbury, Thomas ; Butterton, Joan R. ; Iwamoto, Marian ; Yeh, Wendy W. / Pharmacokinetics, Safety, and Tolerability of Single-Dose Elbasvir in Participants with Hepatic Impairment. In: European Journal of Drug Metabolism and Pharmacokinetics. 2017 ; pp. 1-9.
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abstract = "Background: The combination of elbasvir and grazoprevir is approved for the treatment of hepatitis C virus genotype 1 or 4 infection. Objective: To evaluate the pharmacokinetics and safety of single-dose elbasvir 50 mg in participants with hepatic impairment. Methods: Participants with mild, moderate, or severe hepatic impairment and age-, sex-, and weight-matched healthy controls were enrolled in a 3-part, open-label, sequential-panel, single-dose pharmacokinetic study. Blood samples were collected to assess pharmacokinetics. Safety and tolerability were assessed throughout the study. Results: Thirty-four participants were enrolled: eight with mild hepatic impairment, 11 with moderate hepatic impairment, seven with severe hepatic impairment, and eight healthy matched controls. Participants with mild, moderate, and severe hepatic impairment demonstrated a numeric, but not statistically significant, decrease in elbasvir exposure compared with controls, with a mean 39, 28, and 12{\%} decrease in area under the concentration–time curve from time 0 extrapolated to infinity, as well as a 42, 31, and 42{\%} decrease in maximum plasma concentration (Cmax), respectively. The observed median time to Cmax was similar in participants with hepatic impairment and controls. Single-dose administration of elbasvir was well tolerated. Conclusions: The pharmacokinetics of elbasvir after a single, oral 50-mg dose were not clinically meaningfully altered in non–HCV-infected participants with mild, moderate, or severe hepatic dysfunction. However, since elbasvir is currently available only as part of a fixed-dose combination with grazoprevir, the fixed-dose combination should not be administered to patients with moderate or severe hepatic impairment, due to the significantly increased plasma grazoprevir exposures in those populations.",
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T1 - Pharmacokinetics, Safety, and Tolerability of Single-Dose Elbasvir in Participants with Hepatic Impairment

AU - Marshall, William L.

AU - Feng, Hwa Ping

AU - Wenning, Larissa

AU - Garrett, Graigory

AU - Huang, Xiaobi

AU - Liu, Fang

AU - Panebianco, Deborah

AU - Caro, Luzelena

AU - Fandozzi, Christine

AU - Lasseter, Kenneth C.

AU - Preston, Richard A

AU - Marbury, Thomas

AU - Butterton, Joan R.

AU - Iwamoto, Marian

AU - Yeh, Wendy W.

PY - 2017/12/15

Y1 - 2017/12/15

N2 - Background: The combination of elbasvir and grazoprevir is approved for the treatment of hepatitis C virus genotype 1 or 4 infection. Objective: To evaluate the pharmacokinetics and safety of single-dose elbasvir 50 mg in participants with hepatic impairment. Methods: Participants with mild, moderate, or severe hepatic impairment and age-, sex-, and weight-matched healthy controls were enrolled in a 3-part, open-label, sequential-panel, single-dose pharmacokinetic study. Blood samples were collected to assess pharmacokinetics. Safety and tolerability were assessed throughout the study. Results: Thirty-four participants were enrolled: eight with mild hepatic impairment, 11 with moderate hepatic impairment, seven with severe hepatic impairment, and eight healthy matched controls. Participants with mild, moderate, and severe hepatic impairment demonstrated a numeric, but not statistically significant, decrease in elbasvir exposure compared with controls, with a mean 39, 28, and 12% decrease in area under the concentration–time curve from time 0 extrapolated to infinity, as well as a 42, 31, and 42% decrease in maximum plasma concentration (Cmax), respectively. The observed median time to Cmax was similar in participants with hepatic impairment and controls. Single-dose administration of elbasvir was well tolerated. Conclusions: The pharmacokinetics of elbasvir after a single, oral 50-mg dose were not clinically meaningfully altered in non–HCV-infected participants with mild, moderate, or severe hepatic dysfunction. However, since elbasvir is currently available only as part of a fixed-dose combination with grazoprevir, the fixed-dose combination should not be administered to patients with moderate or severe hepatic impairment, due to the significantly increased plasma grazoprevir exposures in those populations.

AB - Background: The combination of elbasvir and grazoprevir is approved for the treatment of hepatitis C virus genotype 1 or 4 infection. Objective: To evaluate the pharmacokinetics and safety of single-dose elbasvir 50 mg in participants with hepatic impairment. Methods: Participants with mild, moderate, or severe hepatic impairment and age-, sex-, and weight-matched healthy controls were enrolled in a 3-part, open-label, sequential-panel, single-dose pharmacokinetic study. Blood samples were collected to assess pharmacokinetics. Safety and tolerability were assessed throughout the study. Results: Thirty-four participants were enrolled: eight with mild hepatic impairment, 11 with moderate hepatic impairment, seven with severe hepatic impairment, and eight healthy matched controls. Participants with mild, moderate, and severe hepatic impairment demonstrated a numeric, but not statistically significant, decrease in elbasvir exposure compared with controls, with a mean 39, 28, and 12% decrease in area under the concentration–time curve from time 0 extrapolated to infinity, as well as a 42, 31, and 42% decrease in maximum plasma concentration (Cmax), respectively. The observed median time to Cmax was similar in participants with hepatic impairment and controls. Single-dose administration of elbasvir was well tolerated. Conclusions: The pharmacokinetics of elbasvir after a single, oral 50-mg dose were not clinically meaningfully altered in non–HCV-infected participants with mild, moderate, or severe hepatic dysfunction. However, since elbasvir is currently available only as part of a fixed-dose combination with grazoprevir, the fixed-dose combination should not be administered to patients with moderate or severe hepatic impairment, due to the significantly increased plasma grazoprevir exposures in those populations.

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