Opinion
In vivo Target Residence Time and Kinetic Selectivity: The Association Rate Constant as Determinant

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In contrast to the traditional focus on drug–target binding affinity, drug–target binding kinetics is increasingly considered as an important selection criterion in drug discovery.

The predominant paradigm considers a long drug–target residence time to be important to increase the duration of target occupancy.

Current drug-candidate selection focuses on compounds with slow target dissociation kinetics, as reflected in the first-order rate constant koff, relative to the rate of elimination of the unbound drug.

Limited diffusion around the target and extensive target binding, as reflected in the second-order rate constant kon, contribute to prolonged target occupancy. This can make the value of kon an important selection criterion in drug development.

It is generally accepted that, in conjunction with pharmacokinetics, the first-order rate constant of target dissociation is a major determinant of the time course and duration of in vivo target occupancy. Here we show that the second-order rate constant of target association can be equally important. On the basis of the commonly used mathematical models for drug–target binding, it is shown that a high target association rate constant can increase the (local) concentration of the drug, which decreases the rate of decline of target occupancy. The increased drug concentration can also lead to increased off-target binding and decreased selectivity. Therefore, the kinetics of both target association and dissociation need to be taken into account in the selection of drug candidates with optimal pharmacodynamic properties.

Section snippets

Optimization of In Vivo Drug–Target Binding Kinetics for Drug Discovery

To optimize the duration of drug action for therapeutic use, developers have primarily focused on modification of pharmacokinetic (see Glossary) parameters. However, an alternative approach is to optimize the duration of drug action by the modification of drug–target binding kinetics.

The target association and dissociation rate constants are important determinants of both the time course and the extent of drug effects and their values can be measured in high-throughput in vitro systems (Box 1).

Drug–Target Binding In Vivo: Where Does It Occur?

The commonly used mathematical models for drug–target binding were analyzed in this study to yield a quantitative insight into the relative impact of drug–target binding kinetics and pharmacokinetics on the time course of target occupancy in vivo. The simplest model considers the situation where drug–target binding and elimination of the unbound drug from the blood or from a tissue that is in fast equilibrium with the blood occur simultaneously. This is schematically represented by Model 1 (

Simultaneous Elimination and Drug–Target Binding: What Is the Difference?

The influence of pharmacokinetics on the role of drug–target binding kinetics has been acknowledged previously. This influence has been summarized in the general paradigm that the rate of drug–target dissociation has to be slower than the rate of elimination of the unbound drug to prolong the duration of target occupancy. However, this general rule does not take into account the possible influence of drug–target binding on unbound drug concentration profiles. The influence of drug–target

Is the Impact of Drug–Target Binding Kinetics Different for Target Binding in a Tissue?

To expand our understanding of drug–target binding, an analysis similar to that conducted for drug–target binding in the blood was performed for drugs that bind only in a specific tissue. The results of this analysis can be found in S3 in the supplemental information online. One of the main differences compared with the analysis for Model 1 is that the drug distribution from the tissue to the central compartment can be rate limiting for Model 2. A high value of kon leads to equal impacts of kon

Optimizing Drug–Target Binding Kinetics: To What End?

For drug–target binding in both plasma and tissue, our analysis indicates that high kon values can decrease the target occupancy decline below the elimination and dissociation rates. However, this increased duration of target occupancy is caused by increased local drug concentrations unless both koff and kon are low. This means that the optimal value for kon depends on the target, the drug class, and the drug-specific pharmacokinetic, pharmacodynamic, and toxicity processes.

If an increased

Concluding Remarks

Comprehensive analysis of the commonly used models for drug–target binding reveals that high drug–target association rate constants result in longer target occupancy than expected on the basis of the drug–target dissociation and drug elimination rate constants. The kon value that separates high and low values of kon increases with increasing target concentration and with decreasing drug elimination and distribution rate constants and can be calculated algebraically. High values of kon, for

Acknowledgments

The authors thank Professor L.A. Peletier for critically reading the manuscript and providing useful feedback. The authors are part of the K4DD consortium, which is supported by the Innovative Medicines Initiative Joint Undertaking (IMI JU) under grant agreement no 115366. The IMI JU is a project supported by the EU's Seventh Framework Programme (FP7/2007–2013) and the European Federation of Pharmaceutical Industries and Associations (EFPIA).

Glossary

Endogenous competition
binding of an endogenous ligand to the same binding site as a drug.
Endogenous ligand
a compound that is naturally present in the body and functions by binding to a certain receptor.
Kinetic selectivity
differential kinetics of a compound for binding to intended and unintended targets. Most often considered beneficial if the residence time on the intended target is longer than the residence time on the unintended target.
Nonspecific binding
drug binding to proteins, lipids, or

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