Third generation turnover model – Nicotinic acid-induced adaptation of insulin and free fatty acids

R. Andersson, T. Kroon, J. Almquist, M. Jirstrand, N.D. Oakes, J. Gabrielsson. In proceedings of the UK Quantitative Systems Pharmacology Network 1st Exchange Workshop, September 5-7, 2016, Surrey, UK.


Nicotinic acid (NiAc) is a potent inhibitor of adipose tissue lipolysis and acute administration results in a rapid reduction of plasma free fatty acid (FFA) concentrations. However, sustained NiAc exposure is associated with tolerance development, with FFA returning to pretreatment levels (complete adaptation).

Furthermore, a major FFA rebound is seen upon abrupt NiAc washout. Although previous mathematical models successfully describe the acute NiAc-FFA concentration-response relationship, complete adaptation following long-term NiAc exposures requires a new model. In the present study, a 3rd generation turnover model has been developed that describes the adaptation in plasma FFA concentrations following long-term NiAc exposures in lean and obese rats. This was accomplished by extensively modifying previous NiAc-FFA models, resulting in a more general model which is able to capture FFA responses following both acute and repeated NiAc exposures. Specifically, insulin was incorporated alongside NiAc as a co-driver of FFA dynamics. Moreover, the drug-induced efficacy in the system was modelled as a flexible mechanistic function which allowed the system to attain complete adaptation upon sustained NiAc exposure. The pharmacokinetic/pharmacodynamic (PK/PD) models were challenged with an extensive pre-clinical data set comprising a variety of different NiAc provocations. NiAc infusions ranged from 1 h to 5 days, including continuous (24 h/day) and intermittent (12 h/day) protocols, achieved using 19 implantable, programmable mini-pumps. In addition, an engineered gradual NiAc withdrawal protocol was explored as a means of attenuating FFA rebound development. Remarkably, FFA rebound was actually increased during gradual NiAc withdrawal, likely due to NiAc-induced inhibition of insulin secretion; highlighting the importance of including endogenous agonists when modelling metabolic systems. In conclusion, the structure of the 3rd generation turnover model adequately captures a wide range NiAc-induced FFA responses, including acute, intermittent and sustained exposures, and may become a powerful predictive tool to further rationalize NiAc-induced antilipolytic dosing regimens.

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