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

Published

Conference Paper

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.

Full Text

Duke Authors

Cited Authors

  • Gerhart, JG; Watt, KM; Edginton, A; Wade, KC; Salerno, SN; Benjamin, DK; Smith, PB; Hornik, CP; Cohen-Wolkowiez, M; Duara, S; Ross, A; Shattuck, K; Stewart, DL; Neu, N; Gonzalez, D; Best Pharmaceuticals for Children Act-Pediatric Trials Network Steering Committee,

Published Date

  • July 2019

Published In

Volume / Issue

  • 8 / 7

Start / End Page

  • 500 - 510

PubMed ID

  • 31087536

Pubmed Central ID

  • 31087536

Electronic International Standard Serial Number (EISSN)

  • 2163-8306

Digital Object Identifier (DOI)

  • 10.1002/psp4.12414

Conference Location

  • United States