Modeling energy intake by adding homeostatic feedback and drug intervention.
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.
CVMD iMed DMPK AstraZeneca R&D, 431 83, Mölndal, Sweden, Peter.Gennemark@Astrazeneca.com.
Peter
P
Gennemark
Stephan
S
Hjorth
Johan
J
Gabrielsson
D001067:Appetite Depressants / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D002149:Energy Intake / Q000187:drug effects* / Q000502:physiology; D025461:Feedback, Physiological / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008954:Models, Biological; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism; D013997:Time Factors
D001067:Appetite Depressants