To predict in vivo drug effects information on drug-target occupancy is crucial. It is the last step of the processes where drug properties play a role, as after drug-target interaction, signal-transduction and subsequent effects are determined by the system characteristics. In vivo, multiple pharmacokinetic processes occur in parallel, all with their specific rate and extent, and the question is on the role of drug-target binding kinetics in the context of the other pharmacokinetic processes. These processes include plasma pharmacokinetics, tissue pharmacokinetics, target site pharmacokinetics, drug-target interaction (including diffusion-limited binding), competition of the drug with binding of endogenous ligands at the target, and potential target turnover, should be taken into account. Berkeley Madonna and NONMEM simulation were used to investigate the effects of different (combinations of) pharmacokinetic processes as indicated above. This presentation will deal with an overview of the results and insights that have been obtained. In conclusion it can be said that only by integration of the values of rate constants and concentrations in pharmacokinetic processes, we can understand what is rate and extent limiting in target occupancy.

Understanding the influence of drug-target binding kinetics on in vivo drug effects

254th National Meeting (2017)

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