Developing Pharmacokinetic/Pharmacodynamic Relationships With PROTACs

Many examples of PROTACs possessing in vivo efficacy in pre-clinical studies have now been disclosed. While building pharmacokinetic (PK)/pharmacodynamic (PD) relationships is recognized as a key activity in small-molecule drug discovery to support translation from the research to clinical phases, there has been a paucity of reports describing this for PROTACs despite their huge potential as therapeutics. In this chapter we consider the unique mechanism of action of PROTACs and how this introduces additional factors which may need to be considered in the development of PK/PD relationships. We discuss this in the context of a series of PROTACs for the kinase RIPK2, which is a protein with a long half-life. Finally, we discuss how physiologically based pharmacokinetic (PBPK)/PD modeling can be used to deliver human dose predictions with PROTACs.