Population pharmacokinetics of nalmefene in healthy subjects and its relation to μ-opioid receptor occupancy

Abstract

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.

Keywords: alcohol dependence; healthy subjects; nalmefene; opioid antagonist; pharmacodynamics; pharmacokinetics.

Figure 1

Goodness‐of‐fit plots for the final population pharmacokinetic model for nalmefene

Figure 2

Visual predictive check (VPC) plots for the validation dataset for A) day 1 and B) day 5 of dosing. Full lines show median and percentiles (2.5% and 97.5%) of simulated data, while dotted lines show median and percentiles (2.5% and 97.5%) of observed data

Figure 3

Normalized prediction distribution error (NPDE) plots for the validation dataset

Figure 4

Plasma concentration of nalmefene vs. observed and fitted μ‐opioid receptor occupancy

Figure 5

A) Simulated plasma concentration curves of nalmefene and B) simulated duration of μ‐opioid receptor occupancy after a single dose of 20 mg in fed state with 95% confidence bounds