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State-of-the-Art Review on Physiologically Based Pharmacokinetic Modeling in Pediatric Drug Development

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Abstract

Physiologically based pharmacokinetic modeling and simulation is an important tool for predicting the pharmacokinetics, pharmacodynamics, and safety of drugs in pediatrics. Physiologically based pharmacokinetic modeling is applied in pediatric drug development for first-time-in-pediatric dose selection, simulation-based trial design, correlation with target organ toxicities, risk assessment by investigating possible drug–drug interactions, real-time assessment of pharmacokinetic–safety relationships, and assessment of non-systemic biodistribution targets. This review summarizes the details of a physiologically based pharmacokinetic modeling approach in pediatric drug research, emphasizing reports on pediatric physiologically based pharmacokinetic models of individual drugs. We also compare and contrast the strategies employed by various researchers in pediatric physiologically based pharmacokinetic modeling and provide a comprehensive overview of physiologically based pharmacokinetic modeling strategies and approaches in pediatrics. We discuss the impact of physiologically based pharmacokinetic models on regulatory reviews and product labels in the field of pediatric pharmacotherapy. Additionally, we examine in detail the current limitations and future directions of physiologically based pharmacokinetic modeling in pediatrics with regard to the ability to predict plasma concentrations and pharmacokinetic parameters. Despite the skepticism and concern in the pediatric community about the reliability of physiologically based pharmacokinetic models, there is substantial evidence that pediatric physiologically based pharmacokinetic models have been used successfully to predict differences in pharmacokinetics between adults and children for several drugs. It is obvious that the use of physiologically based pharmacokinetic modeling to support various stages of pediatric drug development is highly attractive and will rapidly increase, provided the robustness and reliability of these techniques are well established.

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Authors and Affiliations

  1. Division of Clinical Pharmacology, Department of Pediatrics, University of Utah School of Medicine, 295 Chipeta Way, S100, Salt Lake City, UT, 84108, USA

    Venkata Yellepeddi, Joseph Rower, Xiaoxi Liu, Shaun Kumar, Jahidur Rashid & Catherine M. T. Sherwin

  2. Department of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, University of Utah, Salt Lake City, UT, USA

    Venkata Yellepeddi & Catherine M. T. Sherwin

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  1. Venkata Yellepeddi
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  2. Joseph Rower
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VY, JR, XL, JR, SK, and CS developed the review and wrote the initial draft of the manuscript. Additionally, all authors contributed substantively to the review and revision of the final versions.

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Correspondence to Catherine M. T. Sherwin.

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Venkata Yellepeddi, Joseph Rower, Xiaoxi Liu, Shaun Kumar, Jahidur Rashid, and Catherine M. T. Sherwin have no conflicts of interest directly relevant to the content of this article.

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Yellepeddi, V., Rower, J., Liu, X. et al. State-of-the-Art Review on Physiologically Based Pharmacokinetic Modeling in Pediatric Drug Development. Clin Pharmacokinet 58, 1–13 (2019). https://doi.org/10.1007/s40262-018-0677-y

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