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A Population Physiologically‐Based Pharmacokinetic Model to Characterize Antibody Disposition in Pediatrics and Evaluation of the Model using Infliximab
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  • Hsuan Ping Chang,
  • Valentina Shakhnovich,
  • Adam Frymoyer,
  • Ryan Funk,
  • Mara Becker,
  • K.T. Park,
  • Dhaval Shah
Hsuan Ping Chang
University at Buffalo - The State University of New York
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Valentina Shakhnovich
Children's Mercy Kansas City
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Adam Frymoyer
Stanford Univ
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Mara Becker
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Dhaval Shah
University at Buffalo - The State University of New York
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Abstract

Aims: In order to better predict the pharmacokinetics (PK) of antibodies in children, and to facilitate dose optimization of antibodies in pediatric patients, there is a need to develop systems PK models that integrate ontogeny related changes in human physiological parameters. Methods: A population-based physiological-based PK (PBPK) model to characterize antibody PK in pediatrics has been developed, by incorporating age-related changes in body weight, organ weight, organ blood flow rate, and interstitial volumes in a previously published platform model. The model was further used to perform Monte Carlo simulations to investigate clearance vs. age and dose-exposure relationship for infliximab. Results: By estimating only one parameter and associated interindividual variability, the model was able to characterize clinical PK of infliximab from two pediatric cohorts (n=141, 4-19 years) reasonably well. Model simulations demonstrated that only 50% of children reached desired trough concentrations when receiving FDA-labelled dosing regimen for infliximab, suggesting that higher doses and/or more frequent dosing are needed to achieve target trough concentrations of this antibody. Conclusion: The pediatric PBPK model presented here can serve as a framework to characterize the PK of antibodies in pediatric patients. The model can also be applied to other protein therapeutics to advance precision medicine paradigm and optimize antibody dosing regimens in children.

Peer review status:ACCEPTED

17 Feb 2021Submitted to British Journal of Clinical Pharmacology
18 Feb 2021Submission Checks Completed
18 Feb 2021Assigned to Editor
24 Feb 2021Reviewer(s) Assigned
11 Mar 2021Review(s) Completed, Editorial Evaluation Pending
15 Apr 2021Editorial Decision: Revise Major
14 May 20211st Revision Received
14 May 2021Submission Checks Completed
14 May 2021Assigned to Editor
14 May 2021Review(s) Completed, Editorial Evaluation Pending
23 May 2021Editorial Decision: Accept