title: Pharmacokinetics of long-acting naltrexone in subjects with mild to moderate hepatic impairment.
abstract: Long-acting naltrexone is an extended-release formulation developed with the goal of continuous naltrexone exposure for 1 month for the treatment of alcohol dependence. The influence of mild and moderate hepatic impairment on naltrexone pharmacokinetics following long-acting naltrexone 190-mg administration was assessed. Subjects with mild (Child-Pugh grade A) and moderate (Child-Pugh grade B) hepatic impairment (n = 6 per group) and matched control subjects (n = 13) were enrolled. Naltrexone and 6beta-naltrexol concentrations were determined over a period of 63 days following a single intramuscular dose. Naltrexone and 6beta-naltrexol concentrations were detected in all subjects through 28 days. Total exposure (AUC(0-infinity)) of naltrexone and 6beta-naltrexol was similar across all groups. The long apparent half-lives of naltrexone and 6beta-naltrexol (5-8 days) were attributed to the slow release of naltrexone (long-acting naltrexone exhibits absorption rate-limited elimination or "flip-flop" kinetics); elimination was not altered in subjects with hepatic impairment. Based on pharmacokinetic considerations, the dose of long-acting naltrexone does not need to be adjusted in patients with mild or moderate hepatic impairment.
authors.affiliation: Alkermes, Inc, 88 Sidney Street, Cambridge, MA 02139-4137, USA. Ryan.Turncliff@Alkermes.com
authors.forename: Ryan Z
authors.initials: RZ
authors.lastname: Turncliff
authors.forename: Joi L
authors.initials: JL
authors.lastname: Dunbar
authors.forename: Qunming
authors.initials: Q
authors.lastname: Dong
authors.forename: Bernard L
authors.initials: BL
authors.lastname: Silverman
authors.forename: Elliot W
authors.initials: EW
authors.lastname: Ehrich
authors.forename: Stacy C
authors.initials: SC
authors.lastname: Dilzer
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Lasseter
mesh_terms: D000328:Adult; D000368:Aged; D003692:Delayed-Action Preparations; D005260:Female; D006801:Humans; D008107:Liver Diseases / Q000097:blood / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009271:Naltrexone / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D003692:Delayed-Action Preparations; D009292:Narcotic Antagonists; C010410:6 beta-hydroxynaltrexone; D009271:Naltrexone