Cargando…

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

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Lefebvre, E, Gottwald, M, Lasseter, K, Chang, W, Willett, M, Smith, PF, Somasunderam, A, Utay, NS
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5351328/
https://www.ncbi.nlm.nih.gov/pubmed/27169903
http://dx.doi.org/10.1111/cts.12397
_version_ 1782514755765796864
author Lefebvre, E
Gottwald, M
Lasseter, K
Chang, W
Willett, M
Smith, PF
Somasunderam, A
Utay, NS
author_facet Lefebvre, E
Gottwald, M
Lasseter, K
Chang, W
Willett, M
Smith, PF
Somasunderam, A
Utay, NS
author_sort Lefebvre, E
collection PubMed
description 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‐τ )55%, 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.
format Online
Article
Text
id pubmed-5351328
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher John Wiley and Sons Inc.
record_format MEDLINE/PubMed
spelling pubmed-53513282017-05-23 Pharmacokinetics, Safety, and CCR2/CCR5 Antagonist Activity of Cenicriviroc in Participants With Mild or Moderate Hepatic Impairment Lefebvre, E Gottwald, M Lasseter, K Chang, W Willett, M Smith, PF Somasunderam, A Utay, NS Clin Transl Sci Research 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‐τ )55%, 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. John Wiley and Sons Inc. 2016-05-12 2016-06 /pmc/articles/PMC5351328/ /pubmed/27169903 http://dx.doi.org/10.1111/cts.12397 Text en © 2016 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs (http://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Research
Lefebvre, E
Gottwald, M
Lasseter, K
Chang, W
Willett, M
Smith, PF
Somasunderam, A
Utay, NS
Pharmacokinetics, Safety, and CCR2/CCR5 Antagonist Activity of Cenicriviroc in Participants With Mild or Moderate Hepatic Impairment
title Pharmacokinetics, Safety, and CCR2/CCR5 Antagonist Activity of Cenicriviroc in Participants With Mild or Moderate Hepatic Impairment
title_full Pharmacokinetics, Safety, and CCR2/CCR5 Antagonist Activity of Cenicriviroc in Participants With Mild or Moderate Hepatic Impairment
title_fullStr Pharmacokinetics, Safety, and CCR2/CCR5 Antagonist Activity of Cenicriviroc in Participants With Mild or Moderate Hepatic Impairment
title_full_unstemmed Pharmacokinetics, Safety, and CCR2/CCR5 Antagonist Activity of Cenicriviroc in Participants With Mild or Moderate Hepatic Impairment
title_short Pharmacokinetics, Safety, and CCR2/CCR5 Antagonist Activity of Cenicriviroc in Participants With Mild or Moderate Hepatic Impairment
title_sort pharmacokinetics, safety, and ccr2/ccr5 antagonist activity of cenicriviroc in participants with mild or moderate hepatic impairment
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5351328/
https://www.ncbi.nlm.nih.gov/pubmed/27169903
http://dx.doi.org/10.1111/cts.12397
work_keys_str_mv AT lefebvree pharmacokineticssafetyandccr2ccr5antagonistactivityofcenicrivirocinparticipantswithmildormoderatehepaticimpairment
AT gottwaldm pharmacokineticssafetyandccr2ccr5antagonistactivityofcenicrivirocinparticipantswithmildormoderatehepaticimpairment
AT lasseterk pharmacokineticssafetyandccr2ccr5antagonistactivityofcenicrivirocinparticipantswithmildormoderatehepaticimpairment
AT changw pharmacokineticssafetyandccr2ccr5antagonistactivityofcenicrivirocinparticipantswithmildormoderatehepaticimpairment
AT willettm pharmacokineticssafetyandccr2ccr5antagonistactivityofcenicrivirocinparticipantswithmildormoderatehepaticimpairment
AT smithpf pharmacokineticssafetyandccr2ccr5antagonistactivityofcenicrivirocinparticipantswithmildormoderatehepaticimpairment
AT somasunderama pharmacokineticssafetyandccr2ccr5antagonistactivityofcenicrivirocinparticipantswithmildormoderatehepaticimpairment
AT utayns pharmacokineticssafetyandccr2ccr5antagonistactivityofcenicrivirocinparticipantswithmildormoderatehepaticimpairment