Microdosing and Other Phase 0 Clinical Trials: Facilitating Translation in Drug Development.

Area of Science:

• Pharmacology and Drug Development
• Clinical Trial Design

Background:

• Rising drug development costs and ethical concerns necessitate innovative approaches.
• Microdosing and Phase 0 studies offer solutions to mitigate risks associated with novel chemical entities.

Purpose of the Study:

• To explore the increasing utilization of microdosing and Phase 0 applications in drug development.
• To highlight the versatility and flexibility of these approaches for studying pharmacokinetics (PK), bioavailability, drug-drug interactions (DDI), and pharmacodynamics (PD).

Main Methods:

• Review of current drivers and developments supporting Phase 0 applications.
• Discussion of extrapolation validity from limited exposure to therapeutic exposure using modeling and simulations.
• Examples of specific techniques like Positron Emission Tomography (PET) microdosing and Intra-Target Microdosing (ITM).

Main Results:

• Phase 0 approaches are versatile, enabling studies of PK, bioavailability, DDI, and mechanistic PD.
• PET microdosing facilitates research on target localization, PK, and receptor binding/occupancy.
• ITM allows investigation of local PD effects alongside systemic microdose exposure.

Conclusions:

• Microdosing and Phase 0 studies are valuable for drug development, offering controlled human data to reduce uncertainty.
• These methods are particularly attractive for vulnerable populations and extreme environments due to pharmacotherapy risks.
• The extrapolation of data from limited exposure scenarios to therapeutic intent is crucial for the success of Phase 0 approaches.