Guiding dose selection of monoclonal antibodies using a new parameter (AFTIR) for characterizing ligand binding systems

Abstract

Guiding the dose selection for monoclonal antibody oncology drugs is often done using methods for predicting the receptor occupancy of the drug in the tumor. In this manuscript, previous work on characterizing target inhibition at steady state using the AFIR metric [1] is extended to include a "target-tissue" compartment and the shedding of membrane-bound targets. A new potency metric AFTIR (Averarge Free Tissue target to Initial target ratio at steady state) is derived, and it depends on only four key quantities: the equilibrium binding constant, the fold-change in target expression at steady state after binding to drug, the biodistribution of target from circulation to target tissue, and the average drug concentration in circulation. The AFTIR metric is useful for guiding dose selection, for efficiently performing sensitivity analyses, and for building intuition for more complex target mediated drug disposition models. In particular, reducing the complex, physiological model to four key parameters needed to predict target inhibition helps to highlight specific parameters that are the most important to estimate in future experiments to guide drug development.Guiding dose selection of monoclonal antibodies 3

Beyond Deterministic Models in Drug Discovery and Development

“…From a high-level perspective, PSP involves integrating and quantitatively linking all types of information, methodologies and tools associated with the development of mechanistic models of biological/physiological processes, and pharmacology that can help in our understanding and prediction of drug response in patients. The value of MID3 approaches in decision-making is evidenced by the large number of related publications, recent examples of which can be found in [2][3][4][5]. In these examples, the reliability and explanatory power of the models depend predominantly on the level of detail included and the assumptions on which they are based.…”