Modeling energy intake and body weight effects of a long-acting amylin analogue

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 inves...

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Bibliographic Details
Published in:Journal of pharmacokinetics and pharmacodynamics 2018-04, Vol.45 (2), p.215-233
Main Authors: Brings, Annika, Borghardt, Jens Markus, Skarbaliene, Jolanta, Baader-Pagler, Tamara, Deryabina, Maria A., Rist, Wolfgang, Scheuerer, Stefan
Format: Article
Language:English
Subjects:
Amylin
Analogue
Appetite
Biochemistry
Biomedical and Life Sciences
Biomedical Engineering and Bioengineering
Biomedicine
Body weight
Drug development
Drug dosages
Drug tolerance
Energy
Energy intake
Feedback
Obesity
Original Paper
Pharmacodynamics
Pharmacology/Toxicology
Pharmacy
Rats
Rodents
Studies
Toxicology
Veterinary Medicine/Veterinary Science
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Summary: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.
ISSN:1567-567X
1573-8744
DOI:10.1007/s10928-017-9557-6