title: A modeling approach for compounds affecting body composition.
abstract: Body composition and body mass are pivotal clinical endpoints in studies of welfare diseases. We present a combined effort of established and new mathematical models based on rigorous monitoring of energy intake (EI) and body mass in mice. Specifically, we parameterize a mechanistic turnover model based on the law of energy conservation coupled to a drug mechanism model. Key model variables are fat-free mass (FFM) and fat mass (FM), governed by EI and energy expenditure (EE). An empirical Forbes curve relating FFM to FM was derived experimentally for female C57BL/6 mice. The Forbes curve differs from a previously reported curve for male C57BL/6 mice, and we thoroughly analyse how the choice of Forbes curve impacts model predictions. The drug mechanism function acts on EI or EE, or both. Drug mechanism parameters (two to three parameters) and system parameters (up to six free parameters) could be estimated with good precision (coefficients of variation typically <20 % and not greater than 40 % in our analyses). Model simulations were done to predict the EE and FM change at different drug provocations in mice. In addition, we simulated body mass and FM changes at different drug provocations using a similar model for man. Surprisingly, model simulations indicate that an increase in EI (e.g. 10 %) was more efficient than an equal lowering of EI. Also, the relative change in body mass and FM is greater in man than in mouse at the same relative change in either EI or EE. We acknowledge that this assumes the same drug mechanism impact across the two species. A set of recommendations regarding the Forbes curve, vehicle control groups, dual action on EI and loss, and translational aspects are discussed. This quantitative approach significantly improves data interpretation, disease system understanding, safety assessment and translation across species.
authors.affiliation: CVMD iMED DMPK AstraZeneca R&D, 431 83, Mölndal, Sweden, peter.gennemark@astrazeneca.com.
authors.forename: Peter
authors.initials: P
authors.lastname: Gennemark
authors.forename: Rasmus
authors.initials: R
authors.lastname: Jansson-Löfmark
authors.forename: Gina
authors.initials: G
authors.lastname: Hyberg
authors.forename: Maria
authors.initials: M
authors.lastname: Wigstrand
authors.forename: Dorota
authors.initials: D
authors.lastname: Kakol-Palm
authors.forename: Pernilla
authors.initials: P
authors.lastname: Håkansson
authors.forename: Daniel
authors.initials: D
authors.lastname: Hovdal
authors.forename: Peter
authors.initials: P
authors.lastname: Brodin
authors.forename: Maria
authors.initials: M
authors.lastname: Fritsch-Fredin
authors.forename: Madeleine
authors.initials: M
authors.lastname: Antonsson
authors.forename: Karolina
authors.initials: K
authors.lastname: Ploj
authors.forename: Johan
authors.initials: J
authors.lastname: Gabrielsson
mesh_terms: D000818:Animals; D001067:Appetite Depressants / Q000008:administration & dosage / Q000627:therapeutic use; D001823:Body Composition / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D059305:Diet, High-Fat; D055808:Drug Discovery; D002149:Energy Intake / Q000187:drug effects*; D004734:Energy Metabolism / Q000187:drug effects*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009765:Obesity / Q000378:metabolism* / Q000517:prevention & control
chemical_list: D001067:Appetite Depressants