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Title: Microdosing and Other Phase 0 Clinical Trials: Facilitating Translation in Drug Development

A number of drivers and developments suggest that microdosing and other phase 0 applications will experience increased utilization in the near-to-medium future. Increasing costs of drug development and ethical concerns about the risks of exposing humans and animals to novel chemical entities are important drivers in favor of these approaches, and can be expected only to increase in their relevance. An increasing body of research supports the validity of extrapolation from the limited drug exposure of phase 0 approaches to the full, therapeutic exposure, with modeling and simulations capable of extrapolating even non-linear scenarios. An increasing number of applications and design options demonstrate the versatility and flexibility these approaches offer to drug developers including the study of PK, bioavailability, DDI, and mechanistic PD effects. PET microdosing allows study of target localization, PK and receptor binding and occupancy, while Intra-Target Microdosing (ITM) allows study of local therapeutic-level acute PD coupled with systemic microdose-level exposure. Applications in vulnerable populations and extreme environments are attractive due to the unique risks of pharmacotherapy and increasing unmet healthcare needs. Lastly, all phase 0 approaches depend on the validity of extrapolation from the limited-exposure scenario to the full exposure of therapeutic intent, but in the finalmore » analysis the potential for controlled human data to reduce uncertainty about drug properties is bound to be a valuable addition to the drug development process.« less
Authors:
 [1] ;  [2] ;  [3] ;  [4] ;  [5] ;  [6] ;  [7] ;  [8]
  1. Burt Consultancy, Durham, NC (United States)
  2. US Food and Drug Administration, Silver Spring MD (United States). Center for Drug Evaluation and Research, Office of Clinical Pharmacology (OCP), Office of Translational Sciences; Oak Ridge Inst. for Science and Education (ORISE), Oak Ridge, TN (United States)
  3. Univ. of Lincoln (United Kingdom). School of Pharmacy, Joseph Banks Lab.
  4. LTV Consulting, Davis CA (United States); BioCore, Seoul (South Korea)
  5. US Food and Drug Administration, Silver Spring MD (United States). Center for Drug Evaluation and Research, Office of Clinical Pharmacology (OCP), Office of Translational Sciences
  6. Erasmus MC Sophia Children's Hospital, Rotterdam (The Netherlands)
  7. RIKEN Innovation Center, Yokohama, Kanagawa (Japan). Sugiyama Lab.
  8. Univ. of Manchester (United Kingdom). Centre for Applied Pharmacokinetic Research; Univ. of California, San Francisco, CA (United States). Dept. of Bioengineering and Therapeutic Sciences
Publication Date:
Type:
Accepted Manuscript
Journal Name:
Clinical and Translational Science
Additional Journal Information:
Journal Volume: 9; Journal Issue: 2; Journal ID: ISSN 1752-8054
Research Org:
Oak Ridge Inst. for Science and Education (ORISE), Oak Ridge, TN (United States)
Sponsoring Org:
USDOE Office of Science (SC); Netherlands Organisation for Health Research (ZonMw)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES
OSTI Identifier:
1376052