The AAPS Journal

, Volume 14, Issue 2, pp 262–281 | Cite as

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

  • Peng Zou
  • Yanke Yu
  • Nan Zheng
  • Yongsheng Yang
  • Hayley J. Paholak
  • Lawrence X. Yu
  • Duxin Sun
Review Article


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.


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



This work was partially supported by the National Institutes of Health (RO1 CA120023); University of Michigan Cancer Center Research Grant (Munn); and University of Michigan Cancer Center Core Grant to DS.


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Copyright information

© American Association of Pharmaceutical Scientists 2012

Authors and Affiliations

  1. 1.Department of Pharmaceutical Sciences, College of PharmacyUniversity of MichiganAnn ArborUSA
  2. 2.Office of Testing and Research, Center for Drug Evaluation and ResearchFood and Drug AdministrationSilver SpringUSA
  3. 3.Office of Generic Drugs, Center for Drug Evaluation and ResearchFood and Drug AdministrationRockvilleUSA

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