First Dose in Neonates: Are Juvenile Mice, Adults and In Vitro-In Silico Data Predictive of Neonatal Pharmacokinetics of Fluconazole

W Zhao, C Le Guellec, DK Benjamin, WW Hope, T Bourgeois, KM Watt, John van den Anker, B Matrot, H Saxen, K Hoppu, P Manzoni, E Jacqz-Aigrain

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Background and objectives Selection of the first-dose-in-neonates is challenging. The objective of this proof-of-concept study was to evaluate a pharmacokinetic bridging approach to predict a neonatal dosing regimen. Methods We selected fluconazole as a paradigm compound. We used data from studies in juvenile mice and adults to develop population pharmacokinetic models using NONMEM. We also develop a physiologically-based pharmacokinetic model from in vitro-in silico data using Simcyp. These three models were then used to predict neonatal pharmacokinetics and dosing regimens for fluconazole. Results From juvenile mice to neonates, a correction factor of maximum lifespan potential should be used for extrapolation, while a "renal factor'' taking into account renal maturation was required for successful bridging based on adult and in vitro-in silico data. Simulations results demonstrated that the predicted drug exposure based on bridging approach was comparable to the observed value in neonates. The prediction errors were -2.2, + 10.1 and -4.6 % for juvenile mice, adults and in vitro-in silico data, respectively.
Original languageUndefined/Unknown
Pages (from-to)1005-1018
Number of pages14
JournalClinical Pharmacokinetics
Issue number11
Publication statusPublished - 2014

Research programs

  • EMC MGC-02-53-01-A

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