@article{b42db1203fe94efba11b1b026aeabd27,
title = "Physiologically-Based Pharmacokinetic Modeling of Fluconazole Using Plasma and Cerebrospinal Fluid Samples From Preterm and Term Infants",
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.",
author = "{the Best Pharmaceuticals for Children Act—Pediatric Trials Network Steering Committee} and Gerhart, {Jacqueline G.} and Watt, {Kevin M.} and Andrea Edginton and Wade, {Kelly C.} and Salerno, {Sara N.} and Benjamin, {Daniel K.} and Smith, {P. Brian} and Hornik, {Christoph P.} and Michael Cohen-Wolkowiez and Shahnaz Duara and Ashley Ross and Karen Shattuck and Stewart, {Dan L.} and Natalie Neu and Daniel Gonzalez and Gary Furda and Edmund Capparelli and Kearns, {Gregory L.} and Paul, {Ian M.} and Jan Sullivan and Kelly Wade",
note = "Funding Information: Sciences of the NIH (UL1TR001117), the National Institute of Allergy and Infectious Diseases (HHSN272201500006I and HHSN272201300017I), the NICHD (HHSN275201000003I), the Biomedical Advanced Research and Development Authority (HHSO100201300009C), and other sponsors for drug development in adults and children (www.dcri.duke.edu/ research/coi.jsp). D.G. receives support for research from the NICHD (5K23HD083465). This content is solely the responsibility of the authors and does not represent the official views of the NIH. The remaining authors have no relevant conflicts to disclose. Funding Information: Funding. K.M.W. receives support from the Pediatric Critical Care and Trauma Scientist Development Program (5K12HD047349) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD; 1K23HD075891). A.N.E receives support from the National Institutes of Health (NIH; 1R01-HD076676-01A1). S.N.S. receives support from the NICHD (5T32 GM086330). D.K.B. Jr. receives support from the NIH (2K24HD058735-06), National Center for Advancing Translational Sciences (award UL1TR001117), NICHD contract HHSN275201000003I, and the National Institute of Allergy and Infectious Diseases contract HHSN272201500006I. C.P.H. receives salary support for research from the NICHD (1K23HD090239) and the US government for his work in pediatric and neonatal clinical pharmacology (Government Contract HHSN267200700051C; PI Benjamin under the Best Pharmaceuticals for Children Act) and other sponsors for drug development in adults and children (www.dcri.duke.edu/resea rch/coi.jsp). M.C.-W. receives support for research from the NIH (1R01-HD076676-01A1), the National Center for Advancing Translational Funding Information: K.M.W. receives support from the Pediatric Critical Care and Trauma Scientist Development Program (5K12HD047349) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD; 1K23HD075891). A.N.E receives support from the National Institutes of Health (NIH; 1R01-HD076676-01A1). S.N.S. receives support from the NICHD (5T32 GM086330). D.K.B. Jr. receives support from the NIH (2K24HD058735-06), National Center for Advancing Translational Sciences (award UL1TR001117), NICHD contract HHSN275201000003I, and the National Institute of Allergy and Infectious Diseases contract HHSN272201500006I. C.P.H. receives salary support for research from the NICHD (1K23HD090239) and the US government for his work in pediatric and neonatal clinical pharmacology (Government Contract HHSN267200700051C; PI Benjamin under the Best Pharmaceuticals for Children Act) and other sponsors for drug development in adults and children (www.dcri.duke.edu/research/coi.jsp). M.C.-W. receives support for research from the NIH (1R01-HD076676-01A1), the National Center for Advancing Translational Sciences of the NIH (UL1TR001117), the National Institute of Allergy and Infectious Diseases (HHSN272201500006I and HHSN272201300017I), the NICHD (HHSN275201000003I), the Biomedical Advanced Research and Development Authority (HHSO100201300009C), and other sponsors for drug development in adults and children (www.dcri.duke.edu/research/coi.jsp). Publisher Copyright: {\textcopyright} 2019 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.",
year = "2019",
month = jul,
day = "1",
doi = "10.1002/psp4.12414",
language = "English (US)",
volume = "8",
pages = "500--510",
journal = "CPT: Pharmacometrics and Systems Pharmacology",
issn = "2163-8306",
publisher = "Nature Publishing Group",
number = "7",
}