D. Hovdal(1), J. Gabrielsson(2)
(1) Modelling & Simulation, CVGI iMed DMPK, AstraZeneca R&D Mölndal, Sweden; (2) Department of Biomedical Sciences and Veterinary Public Health, Division of Pharmacology and Toxicology, Box 7028, SE-750 07 Uppsala, Sweden
Objectives: To present a mechanism-based turnover model of body weight change in diet induced obesity (DIO) mice. The model discriminates between system parameters, handling effects (e.g. stress) and drug parameters (affinity, capacity).
Methods: Growth curves of body weight gain were obtained in mice after varying periods on different diets and vehicle and drug (Taranabant) treatment. The drug doses ranged from 0.2 to 20 µmol/kg. The drug exposure was modeled using a two-compartment model with first order absorption. The derived pharmacokinetic parameters were then fixed in the subsequent PKPD analysis of body weight data. Total body weight was analyzed simultaneously with body composition data derived from Dual Energy X-ray Absorptiometry (DEXA) determinations. The mechanism-based turnover model included a first order growth of lean body weight moderated by a physiological limit and a peripheral compartment of tissues readily induced by diet. The vehicle effects were added on parameters reflecting energy intake and the drug induced effects were added on the energy expenditure. All analysis was performed using NONMEM.
Results: A total of 1099 mice, including 20482 observations, were used in the analysis. 102 of these mice were vehicle control animals and another 55 mice were given various doses of drug. The population estimate of in vivo potency of drug was 37 nmol/L (95%CI 12-61 nmol/L) and the half-life of the rapidly induced cells was approximately 17 days in DIO mice.
Conclusions: The proposed mechanism-based turnover model provides practical means of separating vehicle and drug induced changes in body weight and body composition. The model allows analysis of drug- and vehicle (handling) mediated effects via different routes of provocations, such as drugs impacting food intake or energy expenditure. The model can handle different dietary conditions and can account for mice of different strains, age and body compositions.
Reference: PAGE 21 () Abstr 2543 [www.page-meeting.org/?abstract=2543]
Poster: Other Drug/Disease Modelling