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Application of pharmacokinetics–pharmacodynamics/clinical response modeling and simulation for biologics drug development

Authors

  • Liang Zhao,

    Corresponding author
    1. Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland
    • Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland. Telephone: +301-796-5261; Fax: +301-847-8719
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  • Elizabeth Y. Shang,

    1. Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland
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  • Chandrahas G. Sahajwalla

    1. Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland
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  • The views expressed in this chapter are those of the authors and do not reflect the official policy of the US FDA. No official support or endorsement by the US FDA is intended or should be inferred.

Abstract

Biologics, specifically monoclonal antibody (mAb) drugs, have unique pharmacokinetic (PK) and pharmacodynamic (PD) characteristics as opposed to small molecules. Under the paradigm of model-based drug development, PK–PD/clinical response models offer critical insight in guiding biologics development at various stages. On the basis of the molecular structure and corresponding properties of biologics, typical mechanism-based [target-mediated drug disposition (TMDD)], physiologically based PK, PK–PD, and dose–response meta-analysis models are summarized. Examples of using TMDD, PK–PD, and meta-analysis in helping starting dose determination in first-in-human studies and dosing regimen optimization in phase II/III trials are discussed. Instead of covering the entirety of model-based biologics development, this review focuses on the guiding principles and the core mathematical descriptions underlying the PK or PK–PD models most used. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:4367–4382, 2012

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