Introduction: The neonatal population remains one of the populations in which appropriate dosing
regimens are still lacking, resulting in a large off-label or unlicensed use. Clinical research in these small infants
remains a challenge, which sparks the need for modeling and simulation as an additional tool for neonatal drug
Methods: The use of physiologically based pharmacokinetic modeling in preterm and term neonates is investigated.
Results: Throughout the last decade, the use of this modeling technique in this vulnerable population has received
increased attention, but still many knowledge gaps exist. Firstly, an overview of the top-down, bottom-up and
middle-out approach is given, and then these different modeling tools regarding feasibility and appropriate use are
compared. The challenges in applying PBPK to this young population are highlighted and possible solutions are
presented. Examples of applications were found in literature and a preference for the combination of a pure bottom-
up approach with clinical data (the “middle-out” approach) was detected.
Conclusion: Perspectives to further apply this powerful modeling methodology in this population are described in
order to become ‘the tool’ for the design of First-in-Human and First-in-Neonate trials, and the individualization
of dosing in these therapeutic orphans.