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Personalized Dosing of Medicines for Children: A Primer on Pediatric Pharmacometrics for Clinicians

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Abstract

The widespread use of drugs for unapproved purposes remains common in children, primarily attributable to practical, ethical, and financial constraints associated with pediatric drug research. Pharmacometrics, the scientific discipline that involves the application of mathematical models to understand and quantify drug effects, holds promise in advancing pediatric pharmacotherapy by expediting drug development, extending applications, and personalizing dosing. In this review, we delineate the principles of pharmacometrics, and explore its clinical applications and prospects. The fundamental aspect of any pharmacometric analysis lies in the selection of appropriate methods for quantifying pharmacokinetics and pharmacodynamics. Population pharmacokinetic modeling is a data-driven method (‘top-down’ approach) to approximate population-level pharmacokinetic parameters, while identifying factors contributing to inter-individual variability. Model-informed precision dosing is increasingly used to leverage population pharmacokinetic models and patient data, to formulate individualized dosing recommendations. Physiologically based pharmacokinetic models integrate physicochemical drug properties with biological parameters (‘bottom-up approach’), and is particularly valuable in situations with limited clinical data, such as early drug development, assessing drug–drug interactions, or adapting dosing for patients with specific comorbidities. The effective implementation of these complex models hinges on strong collaboration between clinicians and pharmacometricians, given the pivotal role of data availability. Promising advancements aimed at improving data availability encompass innovative techniques such as opportunistic sampling, minimally invasive sampling approaches, microdialysis, and in vitro investigations. Additionally, ongoing research efforts to enhance measurement instruments for evaluating pharmacodynamics responses, including biomarkers and clinical scoring systems, are expected to significantly bolster our capacity to understand drug effects in children.

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Authors and Affiliations

  1. Department of Pediatrics, University of British Columbia, 4480 Oak Street, Vancouver, BC, V6H 3V4, Canada

    Kevin Meesters

  2. Vaccine Evaluation Center, BC Children’s Hospital Research Institute, Vancouver, BC, Canada

    Kevin Meesters

  3. Medical Department, Eli Lilly and Company, Alcobendas, Madrid, Spain

    Violeta Balbas-Martinez

  4. Department of Development and Regeneration, KU Leuven, Leuven, Belgium

    Karel Allegaert

  5. Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium

    Karel Allegaert

  6. Department of Hospital Pharmacy, Erasmus MC, Rotterdam, The Netherlands

    Karel Allegaert

  7. Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Kevin J. Downes

  8. Division of Infectious Diseases, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Kevin J. Downes

  9. Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universität Berlin, Berlin, Germany

    Robin Michelet

  10. qPharmetra LLC, Berlin, Germany

    Robin Michelet

Authors
  1. Kevin Meesters
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  2. Violeta Balbas-Martinez
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  3. Karel Allegaert
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  4. Kevin J. Downes
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  5. Robin Michelet
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Corresponding author

Correspondence to Kevin Meesters.

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Funding

Kevin J. Downes is supported by The Eunice Kennedy Shriver National Institute of Child Health and Human Development (K23HD091365). Kevin Meesters is the recipient of the 2023 Bertram Hoffmeister Postdoctoral Fellowship Award at BC Children’s Hospital Research Institute. The other authors received no additional funding.

Conflicts of Interest/Competing Interests

Violeta Balbas-Martinez is an employee and shareholder of Eli-Lilly and Company. Kevin Meesters, Violeta Balbas-Martinez, Karel Allegaert, Kevin J. Downes, and Robin Michelet have no conflicts of interest that are directly relevant to the content of this article.

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Authors’ Contributions

KM, VB-M, KJD, RM, and KA conceptualized this article, performed the extensive literature review, contributed to the writing of the manuscript, and critically reviewed the manuscript. All authors read and approved the final manuscript as submitted.

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Meesters, K., Balbas-Martinez, V., Allegaert, K. et al. Personalized Dosing of Medicines for Children: A Primer on Pediatric Pharmacometrics for Clinicians. Pediatr Drugs (2024). https://doi.org/10.1007/s40272-024-00633-x

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