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Dose Finding in Single Dose Studies by Allometric Scaling

  • Zheng Lu
  • Rüdiger Kaspera
  • Yoichi Naritomi
  • Tianli Wang
Living reference work entry

Abstract

This chapter reviews common methodologies and applications of scaling for clearance (CL), oral bioavailability (F), volume of distribution (Vd) and half-life (t1/2) with respect to its procedures, evaluation, performance and modifications for the dose finding in single dose studies. Methods of allometric scaling have been well established in drug development to predict the dose for single dose studies for first in human trials from preclinical data, generally from one to three or more species such as mouse, rat, dog or monkey. Allometric scaling is the study of body size to diverse biological characteristics, like clearance. The clearance and other PK parameters are proportional to the body weight among different species. Dose finding in single dose studies by allometric scaling can be either by dose-by-factor approach or pharmacokinetically-guided approach. Besides traditional simple allometry and allometric scaling based on the rule of exponents, many newly proposed methods based on the allometric scaling with different correction factors have been shown either to improve the accuracy of predications or to explore the possibilities of predictions for protein therapeutics. Although the allometric scaling approaches have been widely used to predict human PK parameters of small molecules which is critical to next dose finding step for single ascending dose study, there is a need to have more mechanistic methods based on the allometric scaling, especially for protein therapeutics or some formulations, like liposomal, to improve the predictabilities of first-in-human dose in single ascending dose study.

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Zheng Lu
    • 1
  • Rüdiger Kaspera
    • 2
  • Yoichi Naritomi
    • 3
  • Tianli Wang
    • 1
  1. 1.Clinical Pharmacology and Exploratory DevelopmentAstellas Pharma, NorthbrookILUSA
  2. 2.Clinical Pharmacology and Exploratory DevelopmentAstellas Pharma Europe B.V.LeidenThe Netherlands
  3. 3.Analysis and Pharmacokinetics Research Labs.Astellas Pharma Inc.IbarakiJapan

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