A Population Physiologically‐Based Pharmacokinetic Model to Characterize
Antibody Disposition in Pediatrics and Evaluation of the Model using
Infliximab
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.