Evolution of the drug-target residence time model

ABSTRACT

Introduction

The pharmacological action of a drug is linked to its affinity for a specific molecular target as quantified by in vitro equilibrium measurements. However, it is clear that for many highly effective drugs, interactions with their molecular targets do not conform to simple, equilibrium conditions in vivo and this results in a temporal discordance between pharmacokinetics and pharmacodynamics. The drug-target residence time model was developed to provide a theoretical framework with which to understand cases in which very slow dissociation of the drug-target complex in vivo results in durable PD effects even after systemic concentrations of drug have waned.

Area covered

In this article, the author provides a brief description of the drug-target residence time model and focuses on the refinements that have been made to the original model to incorporate the influences of compound rebinding in cells and pharmacokinetic properties of drug molecules.

Expert opinion

There is now overwhelming evidence for the utility of the drug-target residence time model as a framework for understanding in vivo drug action. The in vitro measured residence time (τ_R) must be used in concert with equilibrium measures of drug-target affinity (e.g. IC₅₀) and with in vivo measures of pharmacokinetic half-life, to afford the researcher a powerful approach to compound optimization for clinical effect. Despite the significant use and refinement of this model, continued studies are required to better understand the dynamic interplay between residence time, target pathobiology, drug distribution and drug pharmacokinetics.

KEYWORDS:

• Residence time
• PK/PD relationship
• durable pharmacology
• drug discovery
• drug optimization
• drug selectivity

Article highlights

• The drug-target residence time model posits that the amplitude and duration of in vivo drug action depends on the length of time that the drug is bound to its target protein; this time period is referred to as the drug target residence time.

• As originally formulated, this model suggests that the best in vitro surrogate measure of in vivo residence time is the reciprocal of the dissociation rate constant for the binary drug-target complex, k_off; the value of 1/k_off is termed the in vitro residence time.

• More recent studies have demonstrated that the intracellular residence time is also impacted by the association rate constant, k_on, and that cellular residence times are often prolonged due to a recurring cycle of slow dissociation of drug from the target and rapid rebinding.

• Recent studies suggest that drug-target residence time becomes a more prominent feature of compounds as they progress towards clinical development.

• Areas for further development of the drug-target residence time model include systematic studies of the structure-kinetic relationships (SKRs) for compounds aimed at better understanding how specific structural features contribute to longer residence times.

Declaration of interest

The author is an employee and shareholder of Accent Therapeutics, Inc. He has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was funded by Accent Therapeutics Inc.