Ehrlich occupancy time: beyond [Formula: see text] to a complete residence time framework

Area of Science:

• Pharmacology
• Biophysics
• Computational Chemistry

Background:

• Drug-target occupancy time is crucial for therapeutic efficacy.
• Existing models like Copeland's residence time neglect key factors such as association rates and drug elimination.
• Paul Ehrlich's principle 'Corpora non agunt nisi fixata' highlights the importance of drugs being bound to targets.

Purpose of the Study:

• To develop a mathematically rigorous framework for Ehrlich occupancy time (EOT).
• To explicitly incorporate association and dissociation kinetics, rebinding, and drug removal into occupancy time calculations.
• To provide quantitative tools for optimizing drug design and predicting in vivo efficacy.

Main Methods:

• Defined EOT as the integral of fractional target occupancy over time.
• Incorporated association (kon) and dissociation (koff) rates, and drug elimination rate (kel).
• Derived mathematical expressions for EOT under various conditions, including equilibrium, ligand excess, induced-fit mechanisms, and first-order drug elimination.

Main Results:

• EOT framework accounts for association, dissociation, rebinding, and drug elimination.
• Under ligand-excess conditions, EOT relates to the dissociation constant (Kd) and drug concentration ([D]).
• For systems with drug elimination, EOT bounds reveal that both binding affinity and elimination rate jointly determine occupancy.
• Copeland's residence time is shown to be a special case of EOT when rebinding is absent.

Conclusions:

• EOT provides a more comprehensive measure of drug-target interaction duration than traditional residence time.
• The framework explains clinical failures of high-affinity drugs due to rapid elimination.
• EOT offers quantitative insights for pharmacokinetic optimization and improved prediction of in vivo drug efficacy.