Modeling of free fatty acid dynamics: insulin and nicotinic acid resistance under acute and chronic treatments
Artikel i vetenskaplig tidskrift, 2017

Nicotinic acid (NiAc) is a potent inhibitor of adipose tissue lipolysis. Acute administration results in a rapid reduction of plasma free fatty acid (FFA) concentrations. Sustained NiAc exposure is associated with tolerance development (drug resistance) and complete adaptation (FFA returning to pretreatment levels). We conducted a meta-analysis on a rich pre-clinical data set of the NiAc-FFA interaction to establish the acute and chronic exposure-response relations from a macro perspective. The data were analyzed using a nonlinear mixed-effects framework. We also developed a new turnover model that describes the adaptation seen in plasma FFA concentrations in lean Sprague-Dawley and obese Zucker rats following acute and chronic NiAc exposure. The adaptive mechanisms within the system were described using integral control systems and dynamic efficacies in the traditional model. Insulin was incorporated in parallel with NiAc as the main endogenous co-variate of FFA dynamics. The model captured profound insulin resistance and complete drug resistance in obese rats. The efficacy of NiAc as an inhibitor of FFA release went from 1 to approximately 0 during sustained exposure in obese rats. The potency of NiAc as an inhibitor of insulin and of FFA release was estimated to be 0.338 and 0.436 , respectively, in obese rats. A range of dosing regimens was analyzed and predictions made for optimizing NiAc delivery to minimize FFA exposure. Given the exposure levels of the experiments, the importance of washout periods in-between NiAc infusions was illustrated. The washout periods should be 2 h longer than the infusions in order to optimize 24 h lowering of FFA in rats. However, the predicted concentration-response relationships suggests that higher AUC reductions might be attained at lower NiAc exposures.

Pharmacology & Pharmacy

niacin

p119

v102

Nonlinear mixed-effects (NLME)

Disease modeling

nmark

identifiability

Turnover models

Meta-analysis

Tolerance

Dosing

puma-g

equations

obese zucker rats

receptor gpr109a

infusions

tolerance

Författare

R. Andersson

The University of Warwick

Stiftelsen Fraunhofer-Chalmers Centrum för Industrimatematik

T. Kroon

AstraZeneca AB

Sveriges lantbruksuniversitet (SLU)

Joachim Almquist

Chalmers, Biologi och bioteknik, Systembiologi

Mats Jirstrand

Stiftelsen Fraunhofer-Chalmers Centrum för Industrimatematik

N. D. Oakes

AstraZeneca AB

N. D. Evans

The University of Warwick

M. J. Chappel

The University of Warwick

J. Gabrielsson

Sveriges lantbruksuniversitet (SLU)

Journal of Pharmacokinetics and Pharmacodynamics

1567-567X (ISSN) 1573-8744 (eISSN)

Vol. 44 3 203-222

Styrkeområden

Building Futures

Livsvetenskaper och teknik

Ämneskategorier

Biologiska vetenskaper

Miljöbioteknik

DOI

10.1007/s10928-017-9512-6