Modeling & Simulation of Long-Term Body Weight Loss during Obesity Pharmacotherapy
Britta Göbel (1), Stefanie Keil (1), Thomas Klabunde (1), Arjun Sanghvi (2), Joachim Tillner (1), Kevin D Hall (2)
(1) Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany; (2) National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
Objectives: Obesity pharmacotherapy can lead to clinically meaningful long-term body weight loss [1]. In early Proof-of-Concept studies, drug effects on body weight are often measured for a period of few weeks only. However, the question arises how body weight changes develop over a long period of treatment, i.e., several years. This knowledge is crucial to decide early in the clinical program, if the targeted weight loss after long-term treatment can be reached. In humans, most obesity drugs work by decreasing metabolizable energy intake. However, quantification of energy intake changes during long-term obesity pharmacotherapy has been prevented by the limitations of self-report methods of measuring energy intake or extrapolation from short-term meal tests [2].
Methods: A validated mathematical model of human metabolism was used to provide the first quantification of metabolizable energy intake changes during long-term obesity pharmacotherapy using body weight data from randomized, placebo-controlled trials that evaluated 14 different drugs or drug combinations [3,4,5,6]. For novel weight reducing drug candidates with a body weight time profile only covering the first weeks of treatment, the long-term body weight loss was estimated applying a quantitative systems pharmacology model.
Results: Changes in metabolizable energy intake during obesity pharmacotherapy were reasonably well described by an exponential pattern, with early large changes in metabolizable energy intake followed by a slow transition to a smaller persistent drug effect. The high correlation between early and late drug effects on energy intake suggests that short-term data can be used to estimate long-term weight outcomes.
Conclusions: Repeated body weight measurements along with a mathematical model of human metabolism can be used to quantify changes in metabolizable energy intake during obesity pharmacotherapy. The calculated metabolizable energy intake changes followed a universal exponential pattern, and hence different drugs can be evaluated and compared using a common mathematical framework. Moreover, the described approach allows translating short-term drug effects into long-term estimations of body weight loss by means of a systems pharmacology approach.
References:
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[2] Schoeller DA, Thomas D, Archer E, et al. Self-report-based estimates of energy intake offer an inadequate basis for scientific conclusions. Am J Clin Nutr 2013;97:1413-1415.
[3] Hall KD, Sacks G, Chandramohan D, et al. Quantification of the effect of energy imbalance on bodyweight. Lancet 2011;378:826-837.
[4] Hall KD, Chow CC. Estimating changes in free-living energy intake and its confidence interval. Am J Clin Nutr 2011;94:66-74.
[5] Sanghvi A, Redman LM, Martin CK, Ravussin E, Hall KD. Validation of an inexpensive and accurate mathematical method to measure long-term changes in free-living energy intake. Am J Clin Nutr. 2015;102(2):353-358.
[6] Goebel B, Sanghvi A, Hall KD. Quantifying Energy Intake Changes During Obesity Pharmacotherapy. Obesity 2014;22(10):2105-2108.
