Effects of target binding kinetics on in vivo drug efficacy: k off , k on and rebinding

Background and Purpose Optimal drug therapy often requires continuing high levels of target occupancy. Besides the traditional pharmacokinetic contribution, target binding kinetics is increasingly considered to play an important role as well. While most attention has been focused on the dissociation rate of the complex, recent reports expressed doubt about the unreserved translatability of this pharmacodynamic property into clinical efficacy. ‘Micro’‐pharmacokinetic mechanisms like drug rebinding and partitioning into the cell membrane may constitute a potential fix. Experimental Approach Simulations were based on solving differential equations. Key Results Based on a selected range of association and dissociation rate constants, k on and k off , and rebinding potencies of the drugs as variables, their effects on the temporal in vivo occupancy profile of their targets, after one or multiple repetitive dosings, have here been simulated. Conclusions and Implications Most strikingly, the simulations show that, when rebinding is also taken into account, increasing k on may produce closely the same outcome as decreasing k off when dosing is performed in accordance with the therapeutically most relevant constant [L max ]/ K D ratio paradigm. Also, under certain conditions, rebinding may produce closely the same outcome as invoking slow diffusion of the drug between the plasma compartment and a target‐containing ‘effect’ compartment. Although the present simulations should only be regarded as a ‘proof of principle’, these findings may help pharmacologists and medicinal chemists to devise ex vivo and in vitro binding kinetic assays that are more relevant and translatable to in vivo settings.