title: First dose in neonates: are juvenile mice, adults and in vitro-in silico data predictive of neonatal pharmacokinetics of fluconazole.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, China, wei.zhao@rdb.aphp.fr.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.forename: Chantal
authors.initials: C
authors.lastname: Le Guellec
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Benjamin
authors.forename: William W
authors.initials: WW
authors.lastname: Hope
authors.forename: Thomas
authors.initials: T
authors.lastname: Bourgeois
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Watt
authors.forename: Johannes N
authors.initials: JN
authors.lastname: van den Anker
authors.forename: Boris
authors.initials: B
authors.lastname: Matrot
authors.forename: Harri
authors.initials: H
authors.lastname: Saxen
authors.forename: Kalle
authors.initials: K
authors.lastname: Hoppu
authors.forename: Paolo
authors.initials: P
authors.lastname: Manzoni
authors.forename: Evelyne
authors.initials: E
authors.lastname: Jacqz-Aigrain
mesh_terms: D000293:Adolescent; D000328:Adult; D001741:Black or African American; D000818:Animals; D000831:Animals, Newborn; D001499:Bayes Theorem; D003198:Computer Simulation; D005260:Female; D015725:Fluconazole / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D051379:Mice; D008954:Models, Biological; D011237:Predictive Value of Tests; D044465:White People
chemical_list: D015725:Fluconazole