Phase 0 trials/ Intra-Target-Microdosing (ITM) and the lung: a review

Area of Science:

• Pharmacology
• Clinical Pharmacology
• Drug Discovery

Background:

• The COVID-19 pandemic underscored the need for efficient respiratory disease drug discovery.
• Traditional clinical trials are costly and inefficient, leading to high drug attrition rates.
• Early-stage drug development faces challenges with predicting efficacy and safety.

Purpose of the Study:

• To introduce and evaluate the Intra-Target Microdosing (ITM) approach for early drug development.
• To enhance the collection of pharmacokinetic (PK) and pharmacodynamic (PD) data in Phase 0 trials.
• To improve the efficiency and cost-effectiveness of developing new and repurposed respiratory drugs.

Main Methods:

• Phase 0 trials utilize sub-clinical microdoses for early human testing.
• Traditional methods focus on systemic PK data using techniques like AMS, LC-MS/MS, and PET.
• The ITM approach exposes a small body compartment to local concentrations for PD and target engagement data.

Main Results:

• ITM allows for direct collection of local PD data and target engagement evidence.
• ITM facilitates extrapolation of both systemic PK and PD data.
• This method offers a more robust assessment compared to traditional PK-focused extrapolation.

Conclusions:

• ITM represents a significant advancement for Phase 0 trials, particularly in respiratory medicine.
• The approach promises more efficient and cost-effective drug development, reducing reliance on animal models.
• ITM has the potential to accelerate the study and development of novel and repurposed pulmonary drugs.