Physiologically based pharmacokinetic (PBPK) modeling and simulation in neonatal drug development: how clinicians can contribute

ABSTRACT

Introduction: Legal initiatives to stimulate neonatal drug development should be accompanied by development of valid research tools. Physiologically based (PB)-pharmacokinetic (PK) modeling and simulation are established tools, accepted by regulatory authorities. Consequently, PBPK holds promise to be a strong research tool to support neonatal drug development.

Area covered: The currently available PBPK models still have poor predictive performance in neonates. Using an illustrative approach on distinct PK processes of absorption, distribution, metabolism, excretion, and real-world data in neonates, we provide evidence on the need to further refine available PBPK system parameters through generation and integration of new knowledge. This necessitates cross talk between clinicians and modelers to integrate knowledge (PK datasets, system knowledge, maturational physiology) or test and refine PBPK models.

Expert opinion: Besides refining these models for ‘small molecules’, PBPK model development should also be more widely applied for therapeutic proteins and to determine exposure through breastfeeding. Researchers should also be aware that PBPK modeling in combination with clinical observations can also be used to elucidate age-related changes that are almost impossible to study based on in vivo or in vitro data. This approach has been explored for hepatic biliary excretion, renal tubular activity, and central nervous system exposure.

KEYWORDS:

• Newborn
• neonatal drug development
• physiologically based pharmacokinetics
• system knowledge
• modeling

Article highlights

• Legal initiatives resulted in a significant increase in knowledge on pediatric pharmacotherapy. Because of poor performance of these initiatives in neonates, additional legal efforts were undertaken. Such initiatives should be accompanied by development of research tools to facilitate neonatal drug development.

• Physiologically based (PB)-PK modeling and simulation is an established tool for drug development with a proven track record, up to regulatory acceptance. Consequently, PBPK holds promise to be a reliable tool to improve this poor performance. The currently available PBPK models overall still have poor predictive performance in neonates.

• Using an illustrative approach with examples on absorption, distribution, metabolism, excretion, and real-world data in neonates, we provide evidence on the value, but also the need and feasibility to refine the available PBPK models.

• Progress necessitates contributions of clinicians by generating datasets on PK and maturational physiology to use these datasets to refine PBPK model predictions.

• Besides refining these PBPK models for ‘small molecules’, PBPK should also be considered more frequently for therapeutic proteins and exposure to drugs or exogenous compounds through breastfeeding.

• Clinical researchers should be aware that PBPK modeling in combination with clinical observations can also be used to elucidate maturational and size-related changes that are almost impossible to collect based on in vivo or in vitro data alone. This approach has been explored for hepatic biliary excretion, renal tubular activity, and central nervous system exposure.

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Declaration of interest

A Vermeulen is a part-time employee of Janssen R&D (80%) and holds stock/stock options from Johnson & Johnson. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The research activities and the collaboration between the different researchers involved have been facilitated by the Agency for Innovation by Science and Technology in Flanders (IWT) through the SAFEPEDRUG project [IWT/SBO 130033]. The research activities of A Smits are supported by the Clinical Research and Education Council of the University Hospitals Leuven. P De Cock is supported by the Ghent University Hospital Clinical Research Fund, Belgium.