When to consider intra-target microdosing: physiologically based pharmacokinetic modeling approach to quantitatively identify key factors for observing target engagement
Frontiers in Pharmacology July 25, 2024 Yasunori Aoki, Malcom Rowland, Yuichi Sugiyama
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.