Population pharmacokinetics of nalmefene in healthy subjects and its relation to μ-opioid receptor occupancy.
OBJECTIVE
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.
Clinical & Quantitative Pharmacology, H. Lundbeck A/S, Ottiliavej 9, 2500, Valby, Denmark.
Lars-Erik Broksoe
LE
Kyhl
Quintiles, 6700 W. 115th Street, Overland Park, Kansas, 66211, USA.
Shen
S
Li
Clinical & Quantitative Pharmacology, H. Lundbeck A/S, Ottiliavej 9, 2500, Valby, Denmark.
Kirstine Ullitz
KU
Faerch
Clinical & Quantitative Pharmacology, H. Lundbeck A/S, Ottiliavej 9, 2500, Valby, Denmark.
Birgitte
B
Soegaard
Clinical & Quantitative Pharmacology, H. Lundbeck A/S, Ottiliavej 9, 2500, Valby, Denmark.
Frank
F
Larsen
Clinical & Quantitative Pharmacology, H. Lundbeck A/S, Ottiliavej 9, 2500, Valby, Denmark.
Johan
J
Areberg
D000284:Administration, Oral; D000437:Alcoholism / Q000188:drug therapy; D017321:Clinical Trials, Phase I as Topic; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D064368:Healthy Volunteers; D006801:Humans; D007275:Injections, Intravenous; D008954:Models, Biological; D009271:Naltrexone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors / Q000378:metabolism*
D009292:Narcotic Antagonists; D017450:Receptors, Opioid, mu; D009271:Naltrexone; C038981:nalmefene
alcohol dependence; healthy subjects; nalmefene; opioid antagonist; pharmacodynamics; pharmacokinetics