Plasma Protein Binding as an Optimizable Parameter for In Vivo Efficacy

Plasma protein binding is crucial for understanding pharmacokinetics, pharmacodynamics, and safety. However, it is often not considered to be a primary parameter for optimization in drug design. This study challenges that perspective by revisiting established pharmacokinetic models and analyzing rat pharmacokinetic data of 3357 compounds. Bidirectional strategies for clearance-dependent optimization of plasma protein binding have been elucidated to achieve suitable effective half-lives. The analysis demonstrates that strategically modulating plasma protein binding can enhance drug efficacy and safety, thereby supporting its role as a critical factor in drug design.