Stine Timmermann, Dorrit Østergaard Nilausen and Johan Areberg
H. Lundbeck A/S
Objectives: To present a study design and modelling approach for investigating the contribution to receptor occupancy from active metabolites with longer terminal half-lives than the parent compound and to use model simulations to illustrate the utility of the approach.
Methods: Time-matched plasma concentrations of parent compound, its metabolite, and receptor occupancy data were obtained from 6 subjects in an open label, multiple dose positron emission tomography study. The subjects were dosed once daily for three weeks to obtain steady state of the parent compound. Three PET scans were performed after the last dose: At tmax, at one week, and at two weeks post the last dose, in order to obtain the largest difference between exposures of parent and metabolite. The PK/PD (occupancy) relationship was analysed by an Emax model using non-linear mixed effect modelling implemented in NONMEM 7.2.0 [1]. Plasma concentration of the metabolite was included in the model as a continuous covariate. The performance of the modelling approach was investigated by simulating different receptor-drug systems with varying contributions (receptor affinities) from the metabolite.
Results: The occupancy versus plasma concentrations data of the parent compound were adequately described by an Emax model with additive and proportional inter-individual variability on Emax and EC50, respectively. The residual error model was additive. Including the metabolite plasma concentration data did not improve the model fit significantly. Simulations showed that the design of the study together with the modelling approach can detect contributions from the metabolite also when the metabolite has low receptor affinity compared to the parent compound.
Conclusions: The analysis of the receptor occupancy-PK data showed that the metabolite did not contribute significantly to the receptor occupancy. The simulations supported that the modelling approach can identify contributions to receptors occupancy from the metabolite even when the relative affinity of the metabolite is low.
References:
[1] Beal SL, Sheiner LB, Boeckmann AJ & Bauer RJ (Eds.) NONMEM Users Guides. 1989-2011. Icon Development Solutions, Ellicott City, Maryland, USA.
Reference: PAGE 25 () Abstr 6002 [www.page-meeting.org/?abstract=6002]
Poster: Methodology - New Modelling Approaches