Review Article

The AAPS Journal

, Volume 14, Issue 2, pp 262-281

First online:

Applications of Human Pharmacokinetic Prediction in First-in-Human Dose Estimation

  • Peng ZouAffiliated withDepartment of Pharmaceutical Sciences, College of Pharmacy, University of Michigan
  • , Yanke YuAffiliated withDepartment of Pharmaceutical Sciences, College of Pharmacy, University of Michigan
  • , Nan ZhengAffiliated withDepartment of Pharmaceutical Sciences, College of Pharmacy, University of Michigan
  • , Yongsheng YangAffiliated withOffice of Testing and Research, Center for Drug Evaluation and Research, Food and Drug Administration
  • , Hayley J. PaholakAffiliated withDepartment of Pharmaceutical Sciences, College of Pharmacy, University of Michigan
  • , Lawrence X. YuAffiliated withOffice of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration Email author 
  • , Duxin SunAffiliated withDepartment of Pharmaceutical Sciences, College of Pharmacy, University of Michigan Email author 

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Abstract

Quantitative estimations of first-in-human (FIH) doses are critical for phase I clinical trials in drug development. Human pharmacokinetic (PK) prediction methods have been developed to project the human clearance (CL) and bioavailability with reasonable accuracy, which facilitates estimation of a safe yet efficacious FIH dose. However, the FIH dose estimation is still very challenging and complex. The aim of this article is to review the common approaches for FIH dose estimation with an emphasis on PK-guided estimation. We discuss 5 methods for FIH dose estimation, 17 approaches for the prediction of human CL, 6 methods for the prediction of bioavailability, and 3 tools for the prediction of PK profiles. This review may serve as a practical protocol for PK- or pharmacokinetic/pharmacodynamic-guided estimation of the FIH dose.

KEY WORDS

allometric scaling FIH dose in vitro–in vivo correlations pharmacokinetics prediction