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Dose Finding in Single Dose Studies by Allometric Scaling

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Drug Discovery and Evaluation: Methods in Clinical Pharmacology

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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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Authors and Affiliations

  1. Clinical Pharmacology and Exploratory Development, Astellas Pharma, Northbrook, IL, USA

    Zheng Lu & Tianli Wang

  2. Clinical Pharmacology and Exploratory Development, Astellas Pharma Europe B.V., Leiden, The Netherlands

    Rüdiger Kaspera

  3. Analysis and Pharmacokinetics Research Labs., Astellas Pharma Inc., Ibaraki, Japan

    Yoichi Naritomi

Authors
  1. Zheng Lu
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  2. Rüdiger Kaspera
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  3. Yoichi Naritomi
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  4. Tianli Wang
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Corresponding author

Correspondence to Zheng Lu .

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Editors and Affiliations

  1. CorDynamics , Dieburg, Germany

    Franz J. Hock

  2. CorDynamics , Chicago, Illinois, USA

    Michael R. Gralinski

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Lu, Z., Kaspera, R., Naritomi, Y., Wang, T. (2018). Dose Finding in Single Dose Studies by Allometric Scaling. In: Hock, F., Gralinski, M. (eds) Drug Discovery and Evaluation: Methods in Clinical Pharmacology. Springer, Cham. https://doi.org/10.1007/978-3-319-56637-5_3-1

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  • DOI: https://doi.org/10.1007/978-3-319-56637-5_3-1

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  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-56637-5

  • Online ISBN: 978-3-319-56637-5

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