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Target site occupancy: emerging generalizations from clinical and preclinical studies
Sarah Grimwood1, Paul R Hartig
1Pfizer Inc., Eastern Point Road, Groton, CT 06340, United States. sarah.grimwood@pfizer.com
Pharmacology & Therapeutics
|March 25, 2009
Summary
Drug occupancy for therapeutic effects requires 60-90% for antagonists and varies for agonists based on efficacy. These findings aid drug development and dosing recommendations.
Area of Science:
- Pharmacology
- Neuroscience
- Drug Development
Background:
- Understanding drug target occupancy is crucial for predicting therapeutic effects.
- Previous research has lacked consistent data on the percentage of target sites that need to be occupied by drugs to elicit physiological or therapeutic responses.
Purpose of the Study:
- To determine the required drug target occupancy for therapeutic effects in patients and physiological effects in humans and animals.
- To establish generalizable target occupancy requirements for various drug classes and targets.
Main Methods:
- Utilized Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) in human studies.
- Integrated data from diverse preclinical methodologies to assess target occupancy.
- Analyzed occupancy data for antagonists and agonists across different target classes.
Main Results:
- Antagonists require approximately 60-90% target occupancy for G protein-coupled receptors, neurotransmitter transporters, and ligand-gated ion channels.
- Agonist occupancy requirements vary widely based on intrinsic activity, target reserve, and measured response.
- Low efficacy agonists generally need high occupancy, while high efficacy agonists require low occupancy.
Conclusions:
- Target occupancy requirements are similar for therapeutic effects and physiological responses.
- Factors like target desensitization and endogenous ligand competition influence occupancy needs.
- Target occupancy measurements are vital for optimizing drug development, dosing, and research for novel drug targets.
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