Speaker
Description
A non-monotone dose response is a pharmacokinetic response characterised by stimulation at low dose and inhibition at high dose of the therapeutic compound. This paradoxical phenomenon is observed in many contexts from kinase to immune checkpoint inhibitors in cancer treatment. Two examples of models with this property are presented.
The first is a kinetic model for the action of a kinase inhibitor in the MAPK signalling pathway and demonstrates that the causes could be purely biochemical. This model provides insight on why this non-monotone response resulting in a simple regulatory mechanism could be masked in biochemical assays.
The second example concerns effector T cell reactivation in vitro under the action of therapeutic compounds targeting the PD-1/PD-L1 interaction. TCR-mediated activation diminishes in the presence of PD-1/PD-L1 interaction provided by co-cultured artificial antigen-presenting cells. Upon PD-L1 blockade with tested compounds at different dose concentrations, cellular activation is restored. The resulting dose response curve is non-monotone due to the existence of two separate and antagonizing effects: first, specific activation of T cells and second, unspecific toxicity that overlap for a certain range of the tested compound concentration.
Parameters of the model are estimated from experimental data and used to provide the EC50 concentration and the maximal safe drug concentration corresponding to the maximum T cell activation.
