Intra-Target Microdosing - A Novel Drug Development Approach: Proof of Concept, Safety, and Feasibility Study in...

Area of Science:

• Pharmacology
• Drug Development
• Clinical Research

Background:

• First-in-human (FIH) testing of new molecular entities (NMEs) requires efficient and safe methodologies.
• Intra-Target Microdosing (ITM) is a novel approach combining direct drug delivery and subpharmacological systemic exposure.
• ITM aims to achieve therapeutic levels at the target site with minimal systemic exposure, particularly for small target tissues.

Purpose of the Study:

• To establish proof-of-concept for ITM in a human model.
• To assess the feasibility and safety of ITM for drug development.
• To evaluate the pharmacokinetic and pharmacodynamic differences between ITM and systemic administration.

Main Methods:

• Five healthy male volunteers participated in a crossover study.
• Participants received either an insulin microdose via radial artery injection or a full therapeutic dose intravenously in separate visits.
• Insulin and glucose levels were measured, alongside 18F-fluorodeoxyglucose (FDG) uptake via Positron Emission Tomography (PET) imaging.

Main Results:

• Insulin and glucose levels in the ipsilateral (treated) hand were comparable between ITM and systemic administration.
• A localized reduction in glucose levels was observed in the ipsilateral hand following ITM, but not in the contralateral hand.
• PET imaging revealed distinct differences in FDG uptake between the ipsilateral and contralateral arms, indicating targeted effects.
• The ITM procedures were found to be safe and well-tolerated by all participants.

Conclusions:

• The study provides proof-of-concept for Intra-Target Microdosing (ITM).
• ITM demonstrates ethical, regulatory, and logistical feasibility for early-stage drug development.
• This approach holds potential for increasing the efficiency of first-in-human testing of new molecular entities.