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, 6 beta-naltrexol, in subpopulations with a potential for alcohol dependence treatment. Method: 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 6 beta-naltrexol were modeled as one-compartment disposition submudels, 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); 6pnaltrexol 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 (losing adjustments of XR-NTX based on weight, age, gender, health status, smoking status, creatinine CL, and hepatic function differences should not be necessary.
