Turn On, Tune In, Turnover! Target Biology Impacts In Vivo Potency, Efficacy, and Clearance

Area of Science:

• Pharmacology and Drug Development
• Biochemical Kinetics
• Translational Medicine

Background:

• Significant knowledge gaps persist in defining determinants of in vivo drug potency and clearance.
• Existing models often lack the integration of crucial biological system dynamics.
• Optimizing translational dose-concentration-response predictions requires a deeper understanding of these determinants.

Purpose of the Study:

• To develop novel open model expressions for in vivo potency and efficacy parameters that incorporate target turnover.
• To analyze the commonalities and differences between potency and efficacy parameters within these new models.
• To comprehensively review literature on factors influencing target turnover rates in biological systems.

Main Methods:

• Derivation of new open model expressions integrating system and drug properties, including target turnover, binding, and complex kinetics.
• Examination of these open models to elucidate the relationships between potency, efficacy, and drug exposure.
• Conducting a comprehensive literature review on the variability of target turnover rates across different biological contexts.

Main Results:

• Fractional turnover rates, rather than absolute target or ligand-target complex concentrations, dictate necessary drug exposure for in vivo potency.
• Absolute ligand-target concentrations, along with transduction and in vivo efficacy parameters, determine the drug's requirement.
• Free enzyme concentration influences clearance and metabolic rate, while fractional turnover rate governs equilibrium kinetics.

Conclusions:

• The novel open model provides a more accurate framework for predicting drug behavior by integrating target turnover.
• Understanding target turnover variability is crucial for optimizing drug discovery, development, and clinical dosing strategies.
• This approach may explain inter-individual differences in drug response and requirements.