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-τ  55%, 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.
authors.affiliation: Tobira Therapeutics, Inc., South San Francisco, California, USA.
authors.forename: E
authors.initials: E
authors.lastname: Lefebvre
authors.affiliation: Tobira Therapeutics, Inc., South San Francisco, California, USA.
authors.forename: M
authors.initials: M
authors.lastname: Gottwald
authors.affiliation: Clinical Pharmacology of Miami, Inc., Miami, Florida, USA.
authors.forename: K
authors.initials: K
authors.lastname: Lasseter
authors.affiliation: Tobira Therapeutics, Inc., South San Francisco, California, USA.
authors.forename: W
authors.initials: W
authors.lastname: Chang
authors.affiliation: Ready Clinical, LLC, Princeton, New Jersey, USA.
authors.forename: M
authors.initials: M
authors.lastname: Willett
authors.affiliation: d3 Medicine, LLC, Parsippany, New Jersey, USA.
authors.forename: P F
authors.initials: PF
authors.lastname: Smith
authors.affiliation: University of Texas Medical Branch at Galveston, Galveston, Texas, USA.
authors.forename: A
authors.initials: A
authors.lastname: Somasunderam
authors.affiliation: University of Texas Medical Branch at Galveston, Galveston, Texas, USA.
authors.forename: N S
authors.initials: NS
authors.lastname: Utay
mesh_terms: D018988:Bacterial Translocation / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D016207:Cytokines / Q000378:metabolism; D003710:Demography; D050556:Fatty Acid-Binding Proteins / Q000378:metabolism; D005260:Female; D005408:Flagellin / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D018836:Inflammation Mediators / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D008107:Liver Diseases / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010539:Permeability / Q000187:drug effects; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors*; D019713:Receptors, CCR5 / Q000378:metabolism*; D013454:Sulfoxides; D013997:Time Factors
chemical_list: D015415:Biomarkers; D016207:Cytokines; D050556:Fatty Acid-Binding Proteins; D007093:Imidazoles; D018836:Inflammation Mediators; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D013454:Sulfoxides; D005408:Flagellin; C506967:cenicriviroc