Modeling energy intake and body weight effects of a long-acting amylin analogue
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The inhibitory effect of anti-obesity drugs on energy intake (EI) is counter-acted by feedback regulation of the appetite control circuit leading to drug tolerance. This complicates the design and interpretation of EI studies in rodents that are used for anti-obesity drug development. Here, we investigated a synthetic long-acting analogue of the appetite-suppressing peptide hormone amylin (LAMY) in lean and diet-induced obese (DIO) rats. EI and body weight (BW) were measured daily and LAMY concentrations in plasma were assessed using defined time points following subcutaneous administration of the LAMY at different dosing regimens. Overall, 6 pharmacodynamic (PD) studies including a total of 173 rats were considered in this evaluation. Treatment caused a dose-dependent reduction in EI and BW, although multiple dosing indicated the development of tolerance over time. This behavior could be adequately described by a population model including homeostatic feedback of EI and a turnover model describing the relationship between EI and BW. The model was evaluated by testing its ability to predict BW loss in a toxicology study and was utilized to improve the understanding of dosing regimens for obesity therapy. As such, the model proved to be a valuable tool for the design and interpretation of rodent studies used in anti-obesity drug development.
KeywordsModel-informed drug discovery Obesity Energy intake Amylin analogue Tolerance
The authors would like to thank Hermann Rapp for valuable discussions and Dr. Arno Kalkuhl for providing us with the toxicology study data. Moreover, we like to thank Sidsel Larsen, Charlotte Holtoft, Arne Lindhardt Jensen, Jessica Bedenik and Christina Doll for excellent technical support.
All authors provided critical review of drafts of the manuscript, and read and approved the final version. AB and JB contributed equally to the development of the model, to the interpretation of the modeling results and writing the manuscript. All other authors contributed to the design of the study and interpretation of the data, and supported and reviewed the model compilation.
Compliance with ethical standards
Conflict of interest
Jens M. Borghardt, Wolfgang Rist, Stefan Scheuerer and Tamara Baader-Pagler are employees of Boehringer Ingelheim Pharma GmbH & Co KG. Jolanta Skarbaliene and Maria A. Deryabina are employees of Zealand Pharma A/S. Annika Brings was an employee of Boehringer Ingelheim Pharma GmbH & Co KG at the time of the manuscript creation.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
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