title: Joint feedback analysis modeling of nonesterified fatty acids in obese Zucker rats and normal Sprague-Dawley rats after different routes of administration of nicotinic acid.
abstract: Data were pooled from several studies on nicotinic acid (NiAc) intervention of fatty acid turnover in normal Sprague-Dawley and obese Zucker rats in order to perform a joint PKPD of data from more than 100 normal Sprague-Dawley and obese Zucker rats, exposed to several administration routes and rates. To describe the difference in pharmacodynamic parameters between obese and normal rats, we modified a previously published nonlinear mixed effects model describing tolerance and oscillatory rebound effects of NiAc on nonesterified fatty acids plasma concentrations. An important conclusion is that planning of experiments and dose scheduling cannot rely on pilot studies on normal animals alone. The obese rats have a less-pronounced concentration-response relationship and need higher doses to exhibit desired response. The relative level of fatty acid rebound after cessation of NiAc administration was also quantified in the two rat populations. Building joint normal-disease models with scaling parameter(s) to characterize the "degree of disease" can be a useful tool when designing informative experiments on diseased animals, particularly in the preclinical screen. Data were analyzed using nonlinear mixed effects modeling, for the optimization, we used an improved method for calculating the gradient than the usually adopted finite difference approximation.
authors.affiliation: Fraunhofer-Chalmers Centre, Chalmers Science Park, Göteborg, Sweden; Discovery Statistics, Discovery Sciences, AstraZeneca R&D Mölndal, Mölndal, Sweden.
authors.forename: Sofia
authors.initials: S
authors.lastname: Tapani
authors.forename: Joachim
authors.initials: J
authors.lastname: Almquist
authors.forename: Jacob
authors.initials: J
authors.lastname: Leander
authors.forename: Christine
authors.initials: C
authors.lastname: Ahlström
authors.forename: Lambertus A
authors.initials: LA
authors.lastname: Peletier
authors.forename: Mats
authors.initials: M
authors.lastname: Jirstrand
authors.forename: Johan
authors.initials: J
authors.lastname: Gabrielsson
mesh_terms: D000818:Animals; D004333:Drug Administration Routes; D005230:Fatty Acids, Nonesterified / Q000097:blood* / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000008:administration & dosage* / Q000494:pharmacology*; D008297:Male; D008954:Models, Biological; D009010:Monte Carlo Method; D009525:Niacin / Q000008:administration & dosage* / Q000494:pharmacology*; D009765:Obesity / Q000097:blood* / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker
chemical_list: D005230:Fatty Acids, Nonesterified; D000960:Hypolipidemic Agents; D009525:Niacin
keywords: disease modeling; disease state; feedback; mathematical models; monte carlo; nonesterified fatty acids (NEFAs); nonlinear regression; pharmacodynamics; sensitivity analysis