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
Journal article, 2014

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.

Disease modeling

Monte carlo

Nonlinear regression

Pharmacodynamics

Sensitivity analysis

Nonesterified fatty acids (NEFAs)

Mathematical models

Feedback

Disease state

Author

Joachim Almquist

Chalmers, Chemical and Biological Engineering, Life Sciences, System Biology

Jacob Leander

University of Gothenburg

Chalmers, Mathematical Sciences, Mathematics

Christine Ahlström

Lambertus A. Peletier

Mats Jirstrand

Johan Gabrielsson

Journal of Pharmaceutical Sciences

0022-3549 (ISSN)

Vol. 103 8 2571-2584

Subject Categories

Mathematics

Bioinformatics and Systems Biology

Areas of Advance

Life Science Engineering (2010-2018)

DOI

10.1002/jps.24077

More information

Created

10/8/2017