Controversies in allometric scaling for predicting human drug clearance: An historical problem and reflections on what works and what does not

Huadong Tang, Michael Mayersohn

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

This review focuses on a discussion of the controversies in allometric scaling (AS) for predicting human clearance from a mathematical and statistical perspective. First, a history of allometric scaling in comparative biology and its use in pharmacokinetics are reviewed. It is shown that the application of AS in predicting human clearance values based on a limited number of animal species (typically, 3 or 4) contains fundamental statistical errors from when AS was first introduced from comparative biology. Second, the mathematical nature of various allometrically-based methods is revealed and the soundness of these methods is assessed. It is demonstrated that any of these methods, which incorporate a correction factor in a traditional allometric approach (varying-exponent allometry), not only reduces the statistical power of the allometric analysis, but are also incorrect with regard to aspects of biology. Finally, it is concluded that allometry remains a valuable tool for predicting human clearance, and should be applied in the context of a fixed exponent. However, fixed-exponent allometry does not provide satisfactory accuracy in predicting human clearance, since it is not able to capture the biological differences among species. Therefore, it is recommended that the overall effort in predicting human pharmacokinetics should be directed to the collection and generation of reliable data (both in vitro and in vivo) along with a better understanding of the DMPK properties of the chemical entity.

Original languageEnglish (US)
Pages (from-to)340-350
Number of pages11
JournalCurrent topics in medicinal chemistry
Volume11
Issue number4
DOIs
StatePublished - 2011

Keywords

  • Clearance
  • Fixed-exponent allometry
  • In vitro-in vivo extrapolation
  • Varying-exponent allometry

ASJC Scopus subject areas

  • Drug Discovery

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