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

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.Conclusion: A model-based bridging approach provided consistent predictions of fluconazole pharmacokinetic parameters in neonates and demonstrated the feasibility of this approach to justify the first-dose-in-neonates, based on all data available from different sources (including physiological informations, preclinical studies and adult data), allowing evidence-based decisions of neonatal dose rather than empiricism.

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