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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 and Almquist, Joachim and Leander, Jacob and Ahlström, Christine and Peletier, Lambertus A. and Jirstrand, Mats and Gabrielsson, Johan (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. Journal of Pharmaceutical Sciences. 103:8, 2571-2584
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Official URL: http://dx.doi.org/10.1002/jps.24077

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/Creators:Tapani, Sofia and Almquist, Joachim and Leander, Jacob and Ahlström, Christine and Peletier, Lambertus A. and Jirstrand, Mats and Gabrielsson, Johan
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
Series/Journal:Journal of Pharmaceutical Sciences (0022-3549)
Year of publishing :2014
Volume:103
Number:8
Page range:2571-2584
Number of Pages:14
Publisher:Wiley
ISSN:0022-3549
Language:English
Publication Type:Journal article
Refereed:Yes
Article category:Scientific peer reviewed
Version:Published version
Full Text Status:Public
Agris subject categories.:X Agricola extesions > X38 Human medicine, health, and safety
Subjects:(A) Swedish standard research categories 2011 > 3 Medical and Health Sciences > 301 Basic Medicine > Pharmaceutical Sciences
(A) Swedish standard research categories 2011 > 3 Medical and Health Sciences > 301 Basic Medicine > Other Basic Medicine
Agrovoc terms:pharmacodynamics, fatty acids
Keywords:pharmacodynamics, nonesterified fatty acids (NEFAs), nonlinear regression, disease modeling, feedback, mathematical models, monte carlo, disease state, sensitivity analysis
URN:NBN:urn:nbn:se:slu:epsilon-e-2608
Permanent URL:
http://urn.kb.se/resolve?urn=urn:nbn:se:slu:epsilon-e-2608
Additional ID:
Type of IDID
Web of Science (WoS)000340277700038
ID Code:12098
Faculty:VH - Faculty of Veterinary Medicine and Animal Science
Department:(VH) > Dept. of Biomedical Sciences and Veterinary Public Health
External funders:EU FP4
Deposited By: SLUpub Connector
Deposited On:06 May 2015 06:27
Metadata Last Modified:07 Mar 2016 11:10

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