Experimental design based on mechanistic mathematical modeling of body composition and energy turnover
P. Gennemark
CVGI iMED,DMPK, AstraZeneca R&D Mölndal
Objectives: Experimental studies of drugs related to appetite, metabolism, and energy expenditure often require rigorous monitoring of food intake and body weight. Obviously, such studies are complicated to administrate and associated with high cost. Experimental design is therefore an important issue. Here, we explore how mechanistic dynamic mathematical models of energy balances and body composition can improve the analysis and experimental design of such studies in both pre-clinical and clinical settings.
Methods: We consider a class of dynamical mathematical models of energy turnover that are based on the law of energy conservation and explicitly connected to physiological variables [1-2]. Key model variables include food intake, body weight and composition, energy expenditure (including resting metabolic rate and physical activity) and metabolic fuel selection under various dietary conditions.
Results: Using the models we first confirmed their flexibility to fit data generated for both food intake and body weight. We then investigated under what assumptions time profiles of food intake can be inferred from body weight data only. We identified two main sources of uncertainty: model choice for representing noisy body weight time profiles and empirical based estimation of energy expenditure. We finally investigated how the models can predict long-term (weeks) effect on body weight based on short-term (days) food intake studies. Our analyses indicate that more cost efficient experimental designs are plausible, in particular for scenarios with no or only minor unmonitored drug tolerance development.
Conclusion: Key advantages of a mechanistic model based analysis include improved understanding of the system dynamics, improved ability to predict beyond the data ranges, and potential to significantly improve the experimental design by reducing the study length. For the latter, the risk of tolerance development must be assessed.
References:
[1] Hall KD. Predicting metabolic adaptation, body weight change, and energy intake in humans. Am J Physiol Endocrinol Metab.298(3):E449-66. 2010.
[2] Guo J, Hall KD. Predicting Changes of Body Weight, Body Fat, Energy Expenditure and Metabolic Fuel Selection in C57BL/6 Mice. PLoS ONE 6(1):e15961. 2011.
