Physiologically-Based Pharmacokinetic Modeling of Fluconazole Using Plasma and Cerebrospinal Fluid Samples From Preterm and Term Infants

the Best Pharmaceuticals for Children Act—Pediatric Trials Network Steering Committee

Research output: Contribution to journalArticle

Abstract

Fluconazole is used to treat hematogenous Candida meningoencephalitis in preterm and term infants. To characterize plasma and central nervous system exposure, an adult fluconazole physiologically-based pharmacokinetic (PBPK) model was scaled to infants, accounting for age dependencies in glomerular filtration and metabolism. The model was optimized using 760 plasma samples from 166 infants (median postmenstrual age (range) 28 weeks (24–50)) and 27 cerebrospinal fluid (CSF) samples from 22 infants (postmenstrual age 28 weeks (24–33)). Simulations evaluated achievement of the surrogate efficacy target of area under the unbound concentration-time curve ≥ 400 mg • hour/L over the dosing interval in plasma and CSF using dosing guidelines. Average fold error of predicted concentrations was 0.73 and 1.14 for plasma and CSF, respectively. Target attainment in plasma and CSF was reached faster after incorporating a loading dose of 25 mg/kg. PBPK modeling can be useful in exploring CNS kinetics of drugs in children.

Original languageEnglish (US)
JournalCPT: Pharmacometrics and Systems Pharmacology
DOIs
StatePublished - Jan 1 2019

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Cerebrospinal fluid
Pharmacokinetics
Fluconazole
Premature Infants
Cerebrospinal Fluid
Plasma
Plasmas
Fluid
Term
Modeling
Meningoencephalitis
Target
Candida
Neurology
Metabolism
Filtration
Efficacy
Dose
Drugs
Fold

ASJC Scopus subject areas

  • Modeling and Simulation
  • Pharmacology (medical)

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Physiologically-Based Pharmacokinetic Modeling of Fluconazole Using Plasma and Cerebrospinal Fluid Samples From Preterm and Term Infants. / the Best Pharmaceuticals for Children Act—Pediatric Trials Network Steering Committee.

In: CPT: Pharmacometrics and Systems Pharmacology, 01.01.2019.

Research output: Contribution to journalArticle

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abstract = "Fluconazole is used to treat hematogenous Candida meningoencephalitis in preterm and term infants. To characterize plasma and central nervous system exposure, an adult fluconazole physiologically-based pharmacokinetic (PBPK) model was scaled to infants, accounting for age dependencies in glomerular filtration and metabolism. The model was optimized using 760 plasma samples from 166 infants (median postmenstrual age (range) 28 weeks (24–50)) and 27 cerebrospinal fluid (CSF) samples from 22 infants (postmenstrual age 28 weeks (24–33)). Simulations evaluated achievement of the surrogate efficacy target of area under the unbound concentration-time curve ≥ 400 mg • hour/L over the dosing interval in plasma and CSF using dosing guidelines. Average fold error of predicted concentrations was 0.73 and 1.14 for plasma and CSF, respectively. Target attainment in plasma and CSF was reached faster after incorporating a loading dose of 25 mg/kg. PBPK modeling can be useful in exploring CNS kinetics of drugs in children.",
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