caa a22 4500 605533709 CHVBK 20210128100839.0 cr unu---uuuuu 210128e20150201xx s 000 0 eng 10.1007/s10928-014-9399-4 doi (NATIONALLICENCE)springer-10.1007/s10928-014-9399-4 Modeling energy intake by adding homeostatic feedback and drug intervention [Elektronische Daten] [Peter Gennemark, Stephan Hjorth, Johan Gabrielsson] Energy intake (EI) is a pivotal biomarker used in quantification approaches to metabolic disease processes such as obesity, diabetes, and growth disorders. Eating behavior is however under both short-term and long-term control. This control system manifests itself as tolerance and rebound phenomena in EI, when challenged by drug treatment or diet restriction. The paper describes a model with the capability to capture physiological counter-regulatory feedback actions triggered by energy imbalances. This feedback is general as it handles tolerance to both increases and decreases in EI, and works in both acute and chronic settings. A drug mechanism function inhibits (or stimulates) EI. The deviation of EI relative to a reference level (set-point) serves as input to a non-linear appetite control signal which in turn impacts EI in parallel to the drug intervention. Three examples demonstrate the potential usefulness of the model in both acute and chronic dosing situations. The model shifts the predicted concentration-response relationship rightwardly at lower concentrations, in contrast to models that do not handle functional adaptation. A fourth example further shows that the model may qualitatively explain differences in rate and extent of adaptation in observed EI and its concomitants in both rodents and humans. Springer Science+Business Media New York, 2014 Model-based drug discovery nationallicence Obesity nationallicence Appetite suppression nationallicence Functional adaptation nationallicence Rebound nationallicence Weight reduction nationallicence Weight maintenance nationallicence Gennemark Peter CVMD iMed DMPK AstraZeneca R&D, 431 83, Mölndal, Sweden aut Hjorth Stephan Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy at Gothenburg University, 413 45, Gothenburg, Sweden aut Gabrielsson Johan Division of Pharmacology and Toxicology, Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, 750 07, Uppsala, Sweden aut Journal of Pharmacokinetics and Pharmacodynamics Springer US; http://www.springer-ny.com 42/1(2015-02-01), 79-96 1567-567X 42:1<79 2015 42 10928 https://doi.org/10.1007/s10928-014-9399-4 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s10928-014-9399-4 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Gennemark Peter CVMD iMed DMPK AstraZeneca R&D, 431 83, Mölndal, Sweden aut NATIONALLICENCE 700 1- Hjorth Stephan Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy at Gothenburg University, 413 45, Gothenburg, Sweden aut NATIONALLICENCE 700 1- Gabrielsson Johan Division of Pharmacology and Toxicology, Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, 750 07, Uppsala, Sweden aut NATIONALLICENCE 773 0- Journal of Pharmacokinetics and Pharmacodynamics Springer US; http://www.springer-ny.com 42/1(2015-02-01), 79-96 1567-567X 42:1<79 2015 42 10928