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Research ArticleSpecial Section on Pediatric Drug Disposition and Pharmacokinetics—Minireview

Physiologically Based Pharmacokinetic Modeling in Pediatric Oncology Drug Development

Nathalie Rioux and Nigel J. Waters
Drug Metabolism and Disposition July 2016, 44 (7) 934-943; DOI: https://doi.org/10.1124/dmd.115.068031
Nathalie Rioux
Epizyme Inc., Cambridge, Massachusetts
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Nigel J. Waters
Epizyme Inc., Cambridge, Massachusetts
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Abstract

Childhood cancer represents more than 100 rare and ultra-rare diseases, with an estimated 12,400 new cases diagnosed each year in the United States. As such, this much smaller patient population has led to pediatric oncology drug development lagging behind that for adult cancers. Developing drugs for pediatric malignancies also brings with it a number of unique trial design considerations, including flexible enrollment approaches, age-appropriate formulation, acceptable sampling schedules, and balancing the need for age-stratified dosing regimens, given the smaller patient populations. The regulatory landscape for pediatric pharmacotherapy has evolved with U.S. Food and Drug Administration (FDA) legislation such as the 2012 FDA Safety and Innovation Act. In parallel, regulatory authorities have recommended the application of physiologically based pharmacokinetic (PBPK) modeling, for example, in the recently issued FDA Strategic Plan for Accelerating the Development of Therapies for Pediatric Rare Diseases. PBPK modeling provides a quantitative and systems-based framework that allows the effects of intrinsic and extrinsic factors on drug exposure to be modeled in a mechanistic fashion. The application of PBPK modeling in drug development for pediatric cancers is relatively nascent, with several retrospective analyses of cytotoxic therapies, and latterly for targeted agents such as obatoclax and imatinib. More recently, we have employed PBPK modeling in a prospective manner to inform the first pediatric trials of pinometostat and tazemetostat in genetically defined populations (mixed lineage leukemia–rearranged and integrase interactor-1–deficient sarcomas, respectively). In this review, we evaluate the application of PBPK modeling in pediatric cancer drug development and discuss the important challenges that lie ahead in this field.

Footnotes

    • Received October 22, 2015.
    • Accepted March 1, 2016.
  • ↵1 Current affiliation: H3 Biomedicine, Cambridge, Massachusetts.

  • ↵2 Current affiliation: Syros Pharmaceuticals, Cambridge, Massachusetts.

  • dx.doi.org/10.1124/dmd.115.068031.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 44 (7)
Drug Metabolism and Disposition
Vol. 44, Issue 7
1 Jul 2016
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Research ArticleSpecial Section on Pediatric Drug Disposition and Pharmacokinetics—Minireview

PBPK Modeling in Pediatric Oncology Drug Development

Nathalie Rioux and Nigel J. Waters
Drug Metabolism and Disposition July 1, 2016, 44 (7) 934-943; DOI: https://doi.org/10.1124/dmd.115.068031

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Research ArticleSpecial Section on Pediatric Drug Disposition and Pharmacokinetics—Minireview

PBPK Modeling in Pediatric Oncology Drug Development

Nathalie Rioux and Nigel J. Waters
Drug Metabolism and Disposition July 1, 2016, 44 (7) 934-943; DOI: https://doi.org/10.1124/dmd.115.068031
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  • Article
    • Abstract
    • Introduction
    • Case Studies of PBPK Modeling in Pediatric Oncology
    • Pediatric PBPK Modeling In-House at Epizyme
    • Current Challenges and Limitations in Pediatric PBPK Modeling
    • Summary and Conclusions
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