When to consider intra-target microdosing: physiologically based pharmacokinetic modeling approach to quantitatively identify key factors for observing target engagement

Intra-Target Microdosing (ITM), a Phase 0 clinical approach, can engage targets at levels similar to systemically administered therapeutic doses for certain compounds, but its probability of success notably decreases when the predicted therapeutic dose exceeds 10 mg. Key factors influencing ITM success include lower dissociation constants, higher systemic clearance, and optimal receptor abundance in the target organ. Target tissues with relatively low blood flow rates and high drug clearance capacities are more conducive to successful ITM. The findings highlight the need to consider each drug's unique pharmacokinetic and pharmacodynamic properties alongside the physiological characteristics of the target tissue when determining ITM suitability.

Study at a glance

Abstract

Intra-Target Microdosing (ITM), integral to Phase 0 clinical studies, offers a novel approach in drug development, effectively bridging the gap between preclinical and clinical phases. This methodology is especially relevant in streamlining early drug development stages. Our research utilized a Physiologically Based Pharmacokinetic (PBPK) model and Monte Carlo simulations to examine factors influencing the effectiveness of ITM in achieving target engagement. The study revealed that ITM is capable of engaging targets at levels akin to systemically administered therapeutic doses for specific compounds. However, we also observed a notable decrease in the probability of success when the predicted therapeutic dose exceeds 10 mg. Additionally, our findings identified several critical factors affecting the success of ITM. These encompass both lower dissociation constants, higher systemic clearance and an optimum abundance of receptors in the target organ. Target tissues characterized by relatively low blood flow rates and high drug clearance capacities were deemed more conducive to successful ITM. These insights emphasize the necessity of taking into account each drug’s unique pharmacokinetic and pharmacodynamic properties, along with the physiological characteristics of the target tissue, in determining the suitability of ITM.