Journal
CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY
Volume 8, Issue 7, Pages 500-510Publisher
WILEY
DOI: 10.1002/psp4.12414
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Funding
- Pediatric Critical Care and Trauma Scientist Development Program [5K12HD047349]
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [1K23HD075891]
- National Institutes of Health (NIH) [1R01-HD076676-01A1]
- NICHD [5T32 GM086330, HHSN275201000003I, 1K23HD090239, 5K23HD083465]
- NIH [2K24HD058735-06, 1R01-HD076676--01A1]
- National Center for Advancing Translational Sciences [UL1TR001117]
- National Institute of Allergy and Infectious Diseases [HHSN272201500006I, HHSN272201300017I]
- US government [HHSN267200700051C]
- National Center for Advancing Translational Sciences of the NIH [UL1TR001117]
- Biomedical Advanced Research and Development Authority [HHSO100201300009C]
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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 center dot 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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