Phase I: The First Opportunity for Extrapolation
from Animal Data to Human Exposure

Stephen Curry, Dennis McCarthy, Heleen Heyn, Matthew Marler, and Johan Gabrielsson

Key Words: Phase I, In vitro / in vivo correlation, animal / human correlation, allometric scaling, intrinsic clearance, pharmacokinetic / pharmacodynamic models

SUMMARY

There is a need to make reliable and rapid predictions of human responses from animal pharmacokinetic data. In this chapter, the authors not only cover the usual "ground" of phase I study design, modeling and analysis, but go much further. The authors build a thesis that by understanding and using of models, links may be found between in vitro and in vivo data, and between models linking animal data to Phase I human data. Use and linking of all these types of pharmacokinetic and pharmacodynamic phenomena could facilitate an expedited and more economical process of drug discovery. Existing approaches to in vitro / in vivo correlations for animal experiments, and to correlation between findings in different species, are considered, as are comparisons of pharmacokinetic / pharmacodynamic models both within and between species. A flow chart is presented which highlights the opportunities for feed-back into the drug development process from computer modelling of data. Emphasis is also placed on the current absence of pharmacodynamic models that would link in vitro observations of receptor-mediated effects (both of animal and human origin) to clinical observations in man

Principles and Practice of Pharmaceutical Medicine (A.J.Fletcher et al., eds.), Chapter 10, Chichester, Wiley, 2002.

Phase I

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