The value of target-site physiologically-based pharmacokinetics for high-affinity small molecules: a mechanistic...

For decades, oncology dose selection has been guided by the maximum tolerated dose (MTD) and plasma pharmacokinetics (PK), reflecting assumptions appropriate for classical cytotoxic chemotherapies. However, the advent of high-affinity, targeted therapies, including kinase inhibitors, epigenetic modulators, and radioligands challenges this paradigm. These agents achieve robust target engagement at doses far below the MTD, and systemic plasma concentrations often fail to reflect pharmacologically relevant exposure at tumor or hematologic sites. Physiologically-based pharmacokinetic (PBPK) modeling, extended to incorporate target-site dynamics, offers a mechanistic framework linking dose, systemic exposure, and local pharmacology. By integrating tissue physiology, drug properties, and target interactions, target-site PBPK provides insights into heterogeneous tumor penetration, intracellular distribution, and variable target occupancy that plasma PK alone cannot capture. Clinical examples, such as PSMA-targeted radioligands and tyrosine kinase inhibitors, illustrate how these models can inform rational dose selection, optimize ligand design, and guide individualized therapy. As oncology moves toward mechanism-driven, biology-aligned development, target-site PBPK represents a pivotal tool for translating preclinical insights into patient-specific dosing strategies and for redefining the standard of precision pharmacology.