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Br J Clin Pharmacol ; 81(2): 290-300, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26483076

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.


Subject(s)
Models, Biological , Naltrexone/analogs & derivatives , Narcotic Antagonists/pharmacokinetics , Receptors, Opioid, mu/metabolism , Administration, Oral , Alcoholism/drug therapy , Clinical Trials, Phase I as Topic , Computer Simulation , Dose-Response Relationship, Drug , Healthy Volunteers , Humans , Injections, Intravenous , Naltrexone/administration & dosage , Naltrexone/blood , Naltrexone/pharmacokinetics , Narcotic Antagonists/administration & dosage , Narcotic Antagonists/blood , Receptors, Opioid, mu/antagonists & inhibitors
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