PAGE. Abstracts of the Annual Meeting of the Population Approach Group in Europe.
PAGE 25 (2016) Abstr 3696 [www.page-meeting.org/?abstract=3696]
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Poster: Methodology - New Modelling Approaches
Britta G÷bel (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 . 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 .
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.