PBPK modeling for early clinical study decision making

We are in an exciting era in drug discovery and development where novel targets and complex diseases have introduced a unique druggable space and opportunities for multi-specific medicines. In the past decade, research has moved toward more hard-to-treat diseases and the tolerance for safety and drug interaction risks has been significantly reduced, especially for indications where safe drugs are already on the market. Similarly, there is an expectation in the current landscape to be well-informed about the potential risks associated with developing a given drug prior to the initiation of first-in-human studies, leaving little room for late-stage surprises. This has opened the door to novel opportunities for the application of model-informed drug development (MIDD). Regardless of the stage of drug development, a mechanistic approach can help to identify and evaluate risks associated with bringing a compound to the market, and if identified early in drug development, determine the key experiments that will provide crucial insights at later stages. One of the key elements of the MIDD handbook in drug discovery and development is physiologically based pharmacokinetic (PBPK) modeling. This chapter will focus on current applications of PBPK modeling, and the data required to answer critical questions at different stages of drug development. It will also highlight the challenges faced by PBPK modeling, and opportunities for expanding modeling capabilities in the upcoming years.