Binding kinetics are integral to a medicine's molecular mechanism of action (MMOA), and thereby influence the efficacy, safety, differentiation and duration of action.  Binding kinetics include equilibrium dissociation constants, association rates and dissociation rates that can inform chemical optimization.  Binding kinetics can impact PK/PD relationships depending on the equilibrium state of the system.  Under equilibrium conditions thermodynamic control will drive PK/PD relationships, and equilibrium constants and fractional occupancy will define a pharmacological response. In contrast, competing kinetic rates will define the pharmacological response when a system that is not at equilibrium.  The potential for mechanism-based toxicity (on-target toxicity) is a key determinate to differentiate between the value of equilibrium versus non-equilibrium binding kinetics.  With no potential for mechanism-based toxicity, an insurmountable/irreversible kinetic mechanism is optimal.  An insurmountable/irreversible mechanism is achieved by covalent bond formation or slow, reversible kinetics in a non-equilibrium system.  The insurmountable/irreversible mechanisms will increase the therapeutic index by decreasing the drug concentrations required for efficacy.  When there is potential for mechanism-based toxicity, equilibrium binding kinetics can contribute to a tolerable therapeutic index.  This talk will cover 1) first principles (kinetic versus thermodynamic control) and 2) the effect of binding kinetics on PK/PD behavior.

Binding kinetics in drug action and discovery

248th National Meeting (2014)

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