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Development and Application of a Physiologically-Based Pharmacokinetic Model to Predict the Pharmacokinetics of Therapeutic Proteins from Full-term Neonates to Adolescents

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Abstract

Physiologically-based pharmacokinetic (PBPK) modelling provides an integrated framework to predict the disposition of small molecule drugs in children and is increasingly being used for dose recommendation and optimal design of paediatric studies and in regulatory submissions. Existing paediatric PBPK models can be adopted to describe the disposition of therapeutic proteins (TPs) in children by incorporating information on age-related changes of additional physiological and biological parameters (e.g. endogenous IgG, neonatal Fc receptor, lymph flow). In this study, physiological parameters were collated from literature and evaluated for any age-dependent trends. The age-dependent physiological parameters were used to construct a paediatric PBPK model for TPs. The model was then used to predict the pharmacokinetics of recombinant human erythropoietin (EPO), infliximab, etanercept, basiliximab, anakinra and enfuvirtide in paediatric subjects. The developed paediatric PBPK model predicted the drug concentration-time profiles reasonably well in full-term neonates (clinical PK data only available for EPO), infants, children and adolescents with the ratios of predicted over observed clearance values within 1.5-fold and 25 out of 26 clearance predictions were within 0.8- to 1.25-fold of the observed values. The clinically reported data are required to further assess the predictive accuracy of PK for Fc-containing proteins in term-born children younger than 2 months. This study demonstrates the ability of PBPK models accounting for age-dependent changes in relevant parameters to predict the pharmacokinetics of different types of TPs in paediatrics. The information gained from the PBPK models described here can facilitate our understanding of the complexities of TPs’ disposition during growth and development.

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Data Availability

The Simcyp Simulator is freely available, following completion of the relevant workshop, to approved members of academic institutions and other non-profit organisations for research and teaching purposes.

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Acknowledgments

The authors thank Eleanor Savill for her assistance in the preparation and submission of the article and Dr. Mian Zhang for critical reading of the manuscript.

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  1. Felix Stader

    Present address: University of Basel, Basel, Switzerland

  2. Xian Pan and Felix Stader contributed equally to this work.

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  1. Certara UK Limited, Simcyp Division, Level 2-Acero, 1 Concourse Way, Sheffield, S1 2BJ, UK

    Xian Pan, Khaled Abduljalil, Katherine L. Gill, Trevor N. Johnson, Iain Gardner & Masoud Jamei

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Felix Stader has no conflict of interest to declare. Xian Pan, Khaled Abduljalil, Katherine L. Gill, Trevor N. Johnson, Iain Gardner and Masoud Jamei are employees of Certara UK Limited, Simcyp Division.

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Pan, X., Stader, F., Abduljalil, K. et al. Development and Application of a Physiologically-Based Pharmacokinetic Model to Predict the Pharmacokinetics of Therapeutic Proteins from Full-term Neonates to Adolescents. AAPS J 22, 76 (2020). https://doi.org/10.1208/s12248-020-00460-1

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  • DOI: https://doi.org/10.1208/s12248-020-00460-1

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