Estimating drug potency in the competitive target mediated drug disposition (TMDD) system when the endogenous ligand is included.

Abstract

Abstract Predictions for target engagement are often used to guide drug development. In particular, when selecting the recommended phase 2 dose of a drug that is very safe, and where good biomarkers for response may not exist (e.g. in immuno-oncology), a receptor occupancy prediction could even be the main determinant in justifying the approved dose, as was the case for atezolizumab. The underlying assumption in these models is that when the drug binds its target, it disrupts the interaction between the target and its endogenous ligand, thereby disrupting downstream signaling. However, the interaction between the target and its endogenous binding partner is almost never included in the model. In this work, we take a deeper look at the in vivo system where a drug binds to its target and disrupts the target’s interaction with an endogenous ligand. We derive two simple steady state inhibition metrics (SSIMs) for the system, which provides intuition for when the competition between drug and endogenous ligand should be taken into account for guiding drug development.