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- Title
First Dose in Neonates: Are Juvenile Mice, Adults and In Vitro-In Silico Data Predictive of Neonatal Pharmacokinetics of Fluconazole.
- Authors
Zhao, Wei; Guellec, Chantal; Benjamin, Daniel; Hope, William; Bourgeois, Thomas; Watt, Kevin; Anker, Johannes; Matrot, Boris; Saxen, Harri; Hoppu, Kalle; Manzoni, Paolo; Jacqz-Aigrain, Evelyne
- Abstract
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.
- Subjects
FLUCONAZOLE; PHARMACOKINETICS; DRUG dosage; EFFECT of drugs on newborn infants; LABORATORY mice; IN vitro studies; THERAPEUTICS
- Publication
Clinical Pharmacokinetics, 2014, Vol 53, Issue 11, p1005
- ISSN
0312-5963
- Publication type
Article
- DOI
10.1007/s40262-014-0169-7