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Clin Pharmacokinet. 2014 Nov;53(11):1005-18. doi: 10.1007/s40262-014-0169-7.

First dose in neonates: are juvenile mice, adults and in vitro-in silico data predictive of neonatal pharmacokinetics of fluconazole.

Author information

1
Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, China, wei.zhao@rdb.aphp.fr.

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.

PMID:
25154507
PMCID:
PMC4703886
DOI:
10.1007/s40262-014-0169-7
[Indexed for MEDLINE]
Free PMC Article

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