Abstract
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.