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

ABSTRACT: 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 ?-opioid receptor occupancy by simulations in the target population.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 ?-opioid occupancy.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 ?-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.A robust population PK model for nalmefene was developed. Based on the concentration-occupancy model the ?-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.

SUBMITTER: Kyhl LE

PROVIDER: S-EPMC4833148 | biostudies-other | 2016 Feb

REPOSITORIES: biostudies-other

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

Kyhl Lars-Erik Broksoe LE Li Shen S Faerch Kirstine Ullitz KU Soegaard Birgitte B Larsen Frank F Areberg Johan J

British journal of clinical pharmacology 20160127 2

<h4>Aims</h4>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.<h4>Methods</h4>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 val ...[more]

PMID: 26483076

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Project description:BACKGROUND AND OBJECTIVES:Upadacitinib is a janus kinase (JAK) 1 inhibitor being developed for the treatment of rheumatoid arthritis (RA) and other inflammatory diseases. This work characterized upadacitinib population pharmacokinetics in healthy subjects and RA patients and the effects of covariates on upadacitinib exposure. METHODS:Upadacitinib plasma concentrations (n = 6399) from 107 healthy subjects and 466 RA patients from three phase I and two 12-week RA phase IIb trials (1-48 mg immediate-release doses across studies) were analyzed using non-linear mixed-effects modeling. The models were qualified using bootstrap and stochastic simulations. RESULTS:A two-compartment model with first-order absorption and elimination described upadacitinib pharmacokinetics. Estimates (95% bootstrap confidence interval) for upadacitinib oral clearance, steady-state volume of distribution, absorption lag time, and mean absorption time were 39.7 (37.8-41.5) L/h, 210 (196-231) L, 0.48 (0.47-0.49) h, and 0.08 (0.04-0.12) h, respectively, for a typical healthy male. Matching on other covariates, a 16 and 32% higher upadacitinib area under the concentration-time curve (AUC) was estimated for females relative to males, and for subjects with RA relative to healthy volunteers, respectively. Subjects with RA with mild or moderate renal impairment were estimated to have 16 and 32% higher upadacitinib AUC, respectively, compared with subjects with RA with normal renal function. Upadacitinib clearance was not correlated with body weight. CONCLUSIONS:Upadacitinib pharmacokinetics follow dose-proportional, bi-exponential disposition. A slightly lower upadacitinib clearance is estimated in subjects with RA than in healthy volunteers, consistent with observations for other JAK inhibitors. Other covariates (weight, sex, mild or moderate renal impairment) are not associated with clinically relevant effects on upadacitinib exposure. TRIAL REGISTRATION:ClinicalTrials.gov ( https://clinicaltrials.gov/ ) identifiers: NCT01741493, NCT02066389, and NCT01960855.

Dataset Information

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

Publications

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

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