Skip to main content
SLU publication database (SLUpub)
Research article - Peer-reviewed, 2017

Modeling of free fatty acid dynamics: insulin and nicotinic acid resistance under acute and chronic treatments

Andersson, Robert; Kroon, Tobias; Almquist, Joachim; Jirstrand, Mats; Oakes, Nicholas D.; Evans, Neil D.; Chappel, Michael J.; Gabrielsson, Johan

Abstract

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.

Keywords

Meta-analysis; Turnover models; Nonlinear mixed-effects (NLME); Tolerance; Disease modeling; Dosing regimen

Published in

Journal of Pharmacokinetics and Pharmacodynamics
2017, Volume: 44, number: 3, pages: 203-222
Publisher: SPRINGER/PLENUM PUBLISHERS