A population physiologically‐based pharmacokinetic model to characterize antibody disposition in pediatrics and evaluation of the model using infliximab

Abstract

In order to better predict the pharmacokinetics (PK) of antibodies in children, and to facilitate dose optimization of antibodies in paediatric 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 paediatrics 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 relationships for infliximab. Results: By estimating only one parameter and associated interindividual variability, the model was able to characterize clinical PK of infliximab from two paediatric 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 paediatric PBPK model presented here can serve as a framework to characterize the PK of antibodies in paediatric patients. The model can also be applied to other protein therapeutics to advance precision medicine paradigm and optimize antibody dosing regimens in children.

Physiologically based pharmacokinetic modelling of semaglutide in children and adolescents with healthy and obese body weights

“…However, these approaches do not consider differences in enzyme expression, physiology and exposure response as a function of age in paediatric patients 21 . Therefore, the use of P‐PBPK models for initial dose extrapolation prior to undertaking clinical trials in children has been steadily increasing in the last few years and is recognized as a low/medium impact application of this approach in the recent European Medicines Agency guidelines 60–64 …”

“…21 Therefore, the use of P-PBPK models for initial dose extrapolation prior to undertaking clinical trials in children has been steadily increasing in the last few years and is recognized as a low/medium impact application of this approach in the recent European Medicines Agency guidelines. [60][61][62][63][64] In the present study, the P-PBPK model was developed using best practice with model verification and modification following a predictlearn-confirm paradigm, refining the model based on adult data before undertaking simulations in paediatrics. 61,64 This is the first time The PBPK model for the SC administration was developed on the in-built TCAT model where the local tissue is divided into 3 compartments at the SC injection site: vascular, endosomal and interstitial space.…”