Link between a high k _on for drug binding and a fast clinical action: to be or not to be?

Review articles on binding kinetics essentially focus on drugs that dissociate slowly from their target since this is required for the successful treatment of many pathophysiological conditions. Recently, the therapeutic benefit of a high k _on (i.e. the second order association rate constant) has also been linked to fast association and to a fast clinical action. Other studies, however, called this assertion into question since additional factors, like the dosing paradigm and the binding mechanism, are important as well. The still ongoing reticence about integrating binding kinetics in lead optimization programs motivated us to critically review the link between the drug's kinetic rate constants and their in vitro and in vivo target occupancy profile, with special focus on k _on. The presented simulations tally with a positive link between a drug's effective/observed association rate (which is quite easy to determine in vitro) and the swiftness of its clinical action. On the other hand, the simulations show that the k _on-concept should not be confounded with the effective association process since increasing this parameter only enhances the drug's in vitro and in vivo association under certain conditions: the binding mechanism should be suitable, rebinding (and thus the factors within the target's micro-environment that favour this mechanism) should not be too prominent and the dosage should not be kept in par with the drug's affinity. Otherwise, increasing k _on could be ineffective or even be counter-productive.