General clinical and methodological considerations on the extrapolation of pharmacokinetics and optimization of study protocols for small molecules and monoclonal antibodies in children

Naïm Bouazza*, Aristides Dokoumetzidis, c4c Expert group on Pharmacometrics, Catherijne A.J. Knibbe, Saskia N. de Wildt, Claire Ambery, Pieter A. De Cock, Elke Gasthuys, Frantz Foissac, Saïk Urien, Anna Karin Hamberg, Italo Poggesi, Wei Zhao, An Vermeulen, Joseph F. Standing, Jean Marc Tréluyer

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Pharmacometric modelling plays a key role in both the design and analysis of regulatory trials in paediatric drug development. Studies in adults provide a rich source of data to inform the paediatric investigation plans, including knowledge on drug pharmacokinetics (PK), safety and efficacy. In children, drug disposition differs widely from birth to adolescence but extrapolating adult to paediatric PK, safety and efficacy either with pharmacometric or physiologically based approaches can help design or in some cases reduce the need for clinical studies. Aspects to consider when extrapolating PK include the maturation of drug metabolizing enzyme expression, glomerular filtration, drug excretory systems, and the expression and activity of specific transporters in conjunction with other drug properties such as fraction unbound. Knowledge of these can be used to develop extrapolation tools such as allometric scaling plus maturation functions or physiologically based PK. PK/pharmacodynamic approaches and well-designed clinical trials in children are of key importance in paediatric drug development. In this white paper, state-of-the-art of current methods used for paediatric extrapolation will be discussed. This paper is part of a conect4children implementation of innovative methodologies including pharmacometric and physiologically based PK modelling in clinical trial design/paediatric drug development through dissemination of expertise and expert advice. The suggestions arising from this white paper should define a minimum set of standards in paediatric modelling and contribute to the regulatory science.

Original languageEnglish
Pages (from-to)4985-4996
Number of pages12
JournalBritish Journal of Clinical Pharmacology
Volume88
Issue number12
Early online date18 Oct 2022
DOIs
Publication statusPublished - Dec 2022

Bibliographical note

Funding Information:
c4c (conect4children) is a project funded by the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement no. 777389. Funding information

Publisher Copyright:
© 2022 British Pharmacological Society.

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