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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Translational Pharmacology
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1366160
This article is part of the Research Topic Incorporating Phase 0 Microdosing as a Powerful Tool Into a New Vision of Drug Development View all 5 articles

When to consider Intra-Target Microdosing: Physiologically Based Pharmacokinetic Modeling Approach to Quantitatively Identify Key Factors for Observing Target Engagement

Provisionally accepted
Yasunori Aoki Yasunori Aoki 1,2Malcom Rowland Malcom Rowland 3Yuichi Sugiyama Yuichi Sugiyama 1*
  • 1 Laboratory of Quantitative System Pharmacokinetics/Pharmacodynamics, Faculty of Pharmaceutical Sciences, Josai International University, Togane-shi, Japan
  • 2 Drug Metabolism and Pharmacokinetics, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Mölndal, Sweden
  • 3 Centre for Applied Pharmacokinetic Research, School of Pharmacy, The University of Manchester, Manchester, England, United Kingdom

The final, formatted version of the article will be published soon.

    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 10mg. 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.

    Keywords: Phase 0, PBPK, Modeling and Simulation, pharmacokinetics, Target engagement, Microdose study

    Received: 05 Jan 2024; Accepted: 29 May 2024.

    Copyright: © 2024 Aoki, Rowland and Sugiyama. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Yuichi Sugiyama, Laboratory of Quantitative System Pharmacokinetics/Pharmacodynamics, Faculty of Pharmaceutical Sciences, Josai International University, Togane-shi, Japan

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.