Premium
Population pharmacokinetics of nalmefene in healthy subjects and its relation to μ‐opioid receptor occupancy
Author(s) -
Kyhl LarsErik Broksoe,
Li Shen,
Faerch Kirstine Ullitz,
Soegaard Birgitte,
Larsen Frank,
Areberg Johan
Publication year - 2016
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.12805
Subject(s) - nalmefene , population , pharmacokinetics , medicine , occupancy , pharmacology , naltrexone , opioid , pharmacodynamics , environmental health , receptor , biology , ecology
Aims The aims of this study were to develop a population pharmacokinetic (PK) model to describe the PK of nalmefene in healthy subjects and to relate the exposure of nalmefene to the μ‐opioid receptor occupancy by simulations in the target population. Methods Data from nine phase I studies (243 subjects) with extensive blood sampling were pooled and used for the population PK model building. Data from four other phase I studies (85 subjects) were pooled and used as an external validation dataset. Eight subjects from an imaging study contributed occupancy data and the pharmacokinetic/pharmacodynamic (PK/PD) relationship was modelled. Combining the population PK model and the PK/PD relationship enabled simulations to predict μ‐opioid occupancy. Results A two compartment model with first order absorption best described the nalmefene PK data. The typical subject in the population was estimated to have a systemic clearance of 60.4 l h −1 and a central volume of distribution of 266 l. Absolute oral bioavailability was estimated to 41% without food intake and with food about 53%. Simulation of the μ‐opioid receptor occupancy shows that the 95% confidence bound is within or above 60–90% occupancy for up to 22–24 h after a single dose of 20 mg nalmefene. Conclusions A robust population PK model for nalmefene was developed. Based on the concentration–occupancy model the μ‐opioid receptor occupancy after a single 20 mg dose of nalmefene is predicted to be above the target therapeutic occupancy for about 24 h in about 95% of the target population.