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