Evolution of the drug-target residence time model

Area of Science:

• Pharmacology
• Drug Discovery
• Computational Chemistry

Background:

• Drug efficacy is typically linked to in vitro equilibrium measurements of target affinity.
• In vivo drug action often deviates from equilibrium conditions, causing a disconnect between pharmacokinetics and pharmacodynamics.
• The drug-target residence time model addresses durable pharmacodynamic effects from slow drug-target complex dissociation.

Purpose of the Study:

• To describe the drug-target residence time model.
• To detail refinements incorporating cellular rebinding and drug pharmacokinetic properties.
• To emphasize the model's utility in understanding in vivo drug action.

Main Methods:

• Review of the drug-target residence time model.
• Discussion of model refinements for rebinding and pharmacokinetics.
• Integration of in vitro residence time with equilibrium affinity and in vivo half-life.

Main Results:

• The drug-target residence time model provides a robust framework for in vivo drug action.
• Measured residence time (τR) combined with affinity (IC50) and half-life aids compound optimization.
• Refinements enhance the model's predictive power for clinical effects.

Conclusions:

• The drug-target residence time model is crucial for understanding in vivo pharmacology.
• Integrating residence time, affinity, and pharmacokinetics offers a powerful optimization strategy.
• Further research is needed on residence time, pathobiology, distribution, and pharmacokinetics.