title: Population pharmacokinetics of extended-release injectable naltrexone (XR-NTX) in patients with alcohol dependence.
abstract: OBJECTIVE
  Injectable extended-release naltrexone (XR-NTX; Vivitrol) has recently been approved for the treatment of alcohol dependence. A population pharmacokinetic (PPK) analysis examined the possibility of altered pharmacokinetics for naltrexone and its primary metabolite, 6beta-naltrexol, in subpopulations with a potential for alcohol-dependence treatment.
  
  
  METHODS
  Data from four clinical studies of XR-NTX were pooled. Absorption was modeled as a sequential release in three phases. The pharmacokinetics of naltrexone and 6beta-naltrexol were modeled as one-compartment disposition submodels, parameterized in terms of clearance (CL) and volume of distribution (V). The impact of age, weight, gender, race, hepatic function, renal function, smoking, and alcohol/opioid dependence on PPK parameter estimates was analyzed.
  
  
  RESULTS
  Plasma concentrations were available from 453 subjects. More than half of the subjects (59%) were alcohol dependent, and 27% were dependent on both alcohol and opioids. Naltrexone CL (140 L/h) and V (38,300 L) were dependent on weight (changes of 0.548 L/h/kg and 0.655 L/kg, respectively) and were 23% and 35% higher, respectively, in subjects with alcohol and/or opioid dependence than in healthy subjects. Naltrexone CL also was dependent on age (-0.108 L/h/year); 6beta-naltrexol CL (65.1 L/h) was dependent on creatinine CL (0.229 L/h/ml/minute) and alkaline phosphatase (-0.130 L/h/IU/L), and was increased by 18% in smokers and in alcohol- and/or opioid-dependent subjects.
  
  
  CONCLUSIONS
  Although statistically significant covariate-parameter relationships were identified, they were not considered clinically meaningful, suggesting that dosing adjustments of XR-NTX based on weight, age, gender, health status, smoking status, creatinine CL, and hepatic function differences should not be necessary.
authors.affiliation: Alkermes, Inc., 88 Sidney Street, Cambridge, Massachusetts 02139, USA.
authors.forename: Joi L
authors.initials: JL
authors.lastname: Dunbar
authors.forename: Ryan Z
authors.initials: RZ
authors.lastname: Turncliff
authors.forename: Siobhan C
authors.initials: SC
authors.lastname: Hayes
authors.forename: Colm B
authors.initials: CB
authors.lastname: Farrell
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000437:Alcoholism / Q000188:drug therapy* / Q000378:metabolism; D003692:Delayed-Action Preparations; D005260:Female; D006801:Humans; D007267:Injections; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D009271:Naltrexone / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D009292:Narcotic Antagonists / Q000493:pharmacokinetics*
chemical_list: D003692:Delayed-Action Preparations; D009292:Narcotic Antagonists; C010410:6 beta-hydroxynaltrexone; D009271:Naltrexone