Pharmacokinetics, Safety, and CCR2/CCR5 Antagonist Activity of Cenicriviroc in Participants With Mild or Moderate Hepatic Impairment

E. Lefebvre; M. Gottwald; K. Lasseter; W. Chang; M. Willett; P. F. Smith; A. Somasunderam; N. S. Utay

doi:10.1111/cts.12397

Pharmacokinetics, Safety, and CCR2/CCR5 Antagonist Activity of Cenicriviroc in Participants With Mild or Moderate Hepatic Impairment

E. Lefebvre, M. Gottwald, K. Lasseter, W. Chang, M. Willett, P. F. Smith, A. Somasunderam, N. S. Utay

Internal Medicine

Research output: Contribution to journal › Article › peer-review

46 Scopus citations

Abstract

Cenicriviroc, a dual CCR2/CCR5 antagonist, is being evaluated for treatment of nonalcoholic steatohepatitis and liver fibrosis (CENTAUR; NCT02217475). As it is metabolized by the liver, cenicriviroc was investigated in hepatic-impaired participants for pharmacokinetic changes. Participants with mild-to-moderate hepatic impairment (HI) (Child–Pugh class A (N = 7) or B (N = 8)) and matched controls (N = 15) received cenicriviroc 150 mg once daily for 14 days. Serial blood samples were obtained on Days 1 and 14. Safety, tolerability, and effects on CCR2/CCR5 ligands, cytokines, and bacterial translocation biomarkers were evaluated. Cenicriviroc exposures were increased by moderate HI (AUC_0-τ55%, C_max 29% higher) but were not with mild HI (AUC_0-τ 38%, C_max 40% lower). Cenicriviroc was well tolerated. Rapid and potent CCR2/CCR5 blockade was observed, not associated with increases in hepatic inflammation or bacterial translocation biomarkers. Study findings suggest that cenicriviroc 150 mg can be used in patients with mild-to-moderate HI.

Original language	English (US)
Pages (from-to)	139-148
Number of pages	10
Journal	Clinical and translational science
Volume	9
Issue number	3
DOIs	https://doi.org/10.1111/cts.12397
State	Published - Jun 1 2016

ASJC Scopus subject areas

General Pharmacology, Toxicology and Pharmaceutics
General Biochemistry, Genetics and Molecular Biology
General Neuroscience

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@article{14e1034066a140c6a67a4e8b2a8f49b4,

title = "Pharmacokinetics, Safety, and CCR2/CCR5 Antagonist Activity of Cenicriviroc in Participants With Mild or Moderate Hepatic Impairment",

abstract = "Cenicriviroc, a dual CCR2/CCR5 antagonist, is being evaluated for treatment of nonalcoholic steatohepatitis and liver fibrosis (CENTAUR; NCT02217475). As it is metabolized by the liver, cenicriviroc was investigated in hepatic-impaired participants for pharmacokinetic changes. Participants with mild-to-moderate hepatic impairment (HI) (Child–Pugh class A (N = 7) or B (N = 8)) and matched controls (N = 15) received cenicriviroc 150 mg once daily for 14 days. Serial blood samples were obtained on Days 1 and 14. Safety, tolerability, and effects on CCR2/CCR5 ligands, cytokines, and bacterial translocation biomarkers were evaluated. Cenicriviroc exposures were increased by moderate HI (AUC0-τ55%, Cmax 29% higher) but were not with mild HI (AUC0-τ 38%, Cmax 40% lower). Cenicriviroc was well tolerated. Rapid and potent CCR2/CCR5 blockade was observed, not associated with increases in hepatic inflammation or bacterial translocation biomarkers. Study findings suggest that cenicriviroc 150 mg can be used in patients with mild-to-moderate HI.",

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AU - Gottwald, M.

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AU - Chang, W.

AU - Willett, M.

AU - Smith, P. F.

AU - Somasunderam, A.

AU - Utay, N. S.

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N2 - Cenicriviroc, a dual CCR2/CCR5 antagonist, is being evaluated for treatment of nonalcoholic steatohepatitis and liver fibrosis (CENTAUR; NCT02217475). As it is metabolized by the liver, cenicriviroc was investigated in hepatic-impaired participants for pharmacokinetic changes. Participants with mild-to-moderate hepatic impairment (HI) (Child–Pugh class A (N = 7) or B (N = 8)) and matched controls (N = 15) received cenicriviroc 150 mg once daily for 14 days. Serial blood samples were obtained on Days 1 and 14. Safety, tolerability, and effects on CCR2/CCR5 ligands, cytokines, and bacterial translocation biomarkers were evaluated. Cenicriviroc exposures were increased by moderate HI (AUC0-τ55%, Cmax 29% higher) but were not with mild HI (AUC0-τ 38%, Cmax 40% lower). Cenicriviroc was well tolerated. Rapid and potent CCR2/CCR5 blockade was observed, not associated with increases in hepatic inflammation or bacterial translocation biomarkers. Study findings suggest that cenicriviroc 150 mg can be used in patients with mild-to-moderate HI.

AB - Cenicriviroc, a dual CCR2/CCR5 antagonist, is being evaluated for treatment of nonalcoholic steatohepatitis and liver fibrosis (CENTAUR; NCT02217475). As it is metabolized by the liver, cenicriviroc was investigated in hepatic-impaired participants for pharmacokinetic changes. Participants with mild-to-moderate hepatic impairment (HI) (Child–Pugh class A (N = 7) or B (N = 8)) and matched controls (N = 15) received cenicriviroc 150 mg once daily for 14 days. Serial blood samples were obtained on Days 1 and 14. Safety, tolerability, and effects on CCR2/CCR5 ligands, cytokines, and bacterial translocation biomarkers were evaluated. Cenicriviroc exposures were increased by moderate HI (AUC0-τ55%, Cmax 29% higher) but were not with mild HI (AUC0-τ 38%, Cmax 40% lower). Cenicriviroc was well tolerated. Rapid and potent CCR2/CCR5 blockade was observed, not associated with increases in hepatic inflammation or bacterial translocation biomarkers. Study findings suggest that cenicriviroc 150 mg can be used in patients with mild-to-moderate HI.

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Pharmacokinetics, Safety, and CCR2/CCR5 Antagonist Activity of Cenicriviroc in Participants With Mild or Moderate Hepatic Impairment

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