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Research article - Peer-reviewed, 2014

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

Tapani, Sofia; Almquist, Joachim; Leander, Jacob; Ahlström, Christine; Peletier, Lambertus A.; Jirstrand, Mats; Gabrielsson, Johan


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. (c) 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2571-2584, 2014


pharmacodynamics; nonesterified fatty acids (NEFAs); nonlinear regression; disease modeling; feedback; mathematical models; monte carlo; disease state; sensitivity analysis

Published in

Journal of Pharmaceutical Sciences
2014, volume: 103, number: 8, pages: 2571-2584

Authors' information

Tapani, Sofia
Fraunhofer-Chalmers Centre
Almquist, Joachim
Fraunhofer-Chalmers Centre
Leander, Jacob
Fraunhofer-Chalmers Centre
Ahlström, Christine
Peletier, Lambertus A.
Leiden University
Jirstrand, Mats
Fraunhofer-Chalmers Centre
Gabrielsson, Johan
Swedish University of Agricultural Sciences, Department of Biomedical Science and Veterinary Public Health

Associated SLU-program


UKÄ Subject classification

Pharmaceutical Sciences
Other Basic Medicine

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