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

Phase 0 trials, positioned between preclinical research and phase I, test sub-clinical microdoses in humans to gather early pharmacokinetic, pharmacodynamic, and mechanistic data, improving drug development efficiency and reducing animal testing. Traditional phase 0 trials use sub-therapeutic microdoses administered intravenously, with readouts from accelerator mass spectrometry, liquid chromatography tandem mass spectrometry, and whole-body positron emission tomography. Mathematical models extrapolate pharmacokinetic data for larger doses but are limited for pharmacodynamic and target engagement data. An Intra-Target Microdosing approach exposes a small body compartment to potentially clinically active local concentrations, enabling pharmacodynamic data collection and target engagement evidence, with potential for rapid, cost-effective development of new and repurposed drugs in the pulmonary system.

Study at a glance

Abstract

Abstract The COVID-19 pandemic has highlighted the importance of efficient drug discovery in respiratory disease. The traditional set up of clinical trials is expensive and allows for significant attrition of new drugs, many of which undergo extensive safety testing before being abandoned for lack of efficacy. Phase 0 trials, named as they sit between pre-clinical research and phase I, allow for the testing of sub-clinical microdoses in humans to gather early pharmacokinetic (PK), pharmacodynamic (PD) and mechanistic data, before deciding on which drugs to advance further. This early data can improve the efficiency and cost effectiveness of drug development and reduce the extent of animal testing. Phase 0 trials traditionally have utilised sub-therapeutic microdoses of compounds administered intravenously with readouts focusing on PK - measured using highly sensitive methods such as accelerator mass spectrometry (AMS) and liquid chromatography tandem mass spectrometry (LC-MS/MS) of peripheral blood, as well as whole-body positron emission tomography (PET). Mathematical models allow for extrapolation of this PK data to support the further testing of larger, systemically effective doses. However, this extrapolation method is limited at providing robust PD or target engagement/ mode of action data. Using an Intra-Target Microdosing (ITM) approach, a small compartment of the body (about 1% or less) is exposed to potentially clinically active local concentrations. This allows for the collection of PD data, evidence of target cell engagement, as well as the opportunity to extrapolate systemic PK and PD data. This approach has the potential within the pulmonary system for the study and rapid and cost-effective development of new and repurposed drugs.