Evolution of the drug-target residence time model

Abstract

IntroductionThe pharmacological action of a drug is linked to its affinity for a specific molecular target as quantified by in vitro equilibrium measurements. However, it is clear that for many highly effective drugs, interactions with their molecular targets do not conform to simple, equilibrium conditions in vivo and this results in a temporal discordance between pharmacokinetics and pharmacodynamics. The drug-target residence time model was developed to provide a theoretical framework with which to understand cases in which very slow dissociation of the drug-target complex in vivo results in durable PD effects even after systemic concentrations of drug have waned.Area coveredIn this article, the author provides a brief description of the drug-target residence time model and focuses on the refinements that have been made to the original model to incorporate the influences of compound rebinding in cells and pharmacokinetic properties of drug molecules.Expert opinionThere is now overwhelming evidence for the utility of the drug-target residence time model as a framework for understanding in vivo drug action. The in vitro measured residence time (τ_R) must be used in concert with equilibrium measures of drug-target affinity (e.g. IC₅₀) and with in vivo measures of pharmacokinetic half-life, to afford the researcher a powerful approach to compound optimization for clinical effect. Despite the significant use and refinement of this model, continued studies are required to better understand the dynamic interplay between residence time, target pathobiology, drug distribution and drug pharmacokinetics.

Keywords: PK/PD relationship; Residence time; drug discovery; drug optimization; drug selectivity; durable pharmacology.