Premium
PI‐82
Author(s) -
Hayes S.,
Farrell C.,
Dunbar J.,
Turncliff R.
Publication year - 2006
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2005.12.103
Subject(s) - naltrexone , pharmacokinetics , volume of distribution , medicine , dosing , population , pharmacology , metabolite , covariate , opioid , receptor , statistics , mathematics , environmental health
BACKGROUND Naltrexone (NTX) is used in the treatment of alcohol and opioid dependency. While oral NTX must be given daily, long‐acting naltrexone (LA‐NTX) was designed to provide continuous exposure to NTX for 1 month with a single IM injection. AIMS To characterize the population pharmacokinetics (PPK) of NTX and its major metabolite, 6β‐naltrexol (6β‐NOH), following LA‐NTX administration using nonlinear mixed effects modeling. METHODS Data from 4 clinical studies of LA‐NTX were pooled for the analysis: 3821 NTX and 3766 6β‐NOH plasma samples from 453 subjects were available. One‐compartment disposition submodels, parameterized in terms of clearance (CL) and volume of distribution (V), were used to describe the PK of NTX and 6β‐NOH. Absorption was modelled as sequential release from 3 depot compartments. The impact of covariates (demographics, alcohol/opiate use, renal/hepatic function) on PK parameter estimates was evaluated. RESULTS NTX CL (140 L/h) and V (38800 L) were dependent on weight (0.552 L/h/kg and 0.682 L/kg, respectively); 6β‐NOH CL (64.5 L/h) was dependent on creatinine clearance (0.213 L/h/mL/min). Additionally, NTX CL and V, and 6β‐NOH CL were 24%, 35%, and 30% higher, respectively, in alcohol and/or opioid dependent subjects. These covariate ‐ parameter relationships were not clinically relevant. CONCLUSIONS A PPK model of LA‐NTX describing inter‐ and intra‐individual variability was developed. Dosing adjustments of LA‐NTX should not be necessary for evaluated covariates. Clinical Pharmacology & Therapeutics (2005) 79 , P28–P28; doi: 10.1016/j.clpt.2005.12.103