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.

Clinical pharmacology of fluconazole in infants and children

“…This drug diffuses in all body tissues where reaches effective concentration, and tissue-plasma partition coefficient is 2.03 [3]. Penetration into cerebrospinal fluid is good [38,39] and successfully cured meningitis caused fungemia [40,41], and is the drug of choice for treatment of meningitis caused by Coccidioidal meningitis [2]. Fluconazole also migrates into breast-milk in significant amounts, the estimated relative infant dose is 17% of the maternal dose, and drug half-life is 30 hours in breast-milk, thus it is longer than that of found in healthy volunteers [42].…”

“…Gerhart et al [38] characterized fluconazole exposure in plasma of 22 infants with mean postmenstrual age of 28 weeks (range, 24 to 50), and in cerebrospinal fluid of 27 infants with a mean postmenstrual age of 28 weeks (range, 24 to 33). Cerebrospinal fluid concentration ranged from 0.1 to 9.6 µg/ml and was obtained 3.3 to 219 hours from the last dose.…”

Physiologically‐Based Pharmacokinetic Modeling Characterizes the CYP3A‐Mediated Drug‐Drug Interaction Between Fluconazole and Sildenafil in Infants

“…There were four preterm infants with PK data who received sildenafil with fluconazole. We comodeled sildenafil with fluconazole in preterm infants leveraging a previously published fluconazole PBPK model in adults and infants, including renal clearance and uridine 5′‐disphospho‐glucuronosyltransferase family 2 member B7 (UGT2B7) metabolism 32,35 . Only the indication (prophylaxis vs. treatment) for fluconazole was recorded for these preterm infants.…”

The Blind Spot of Pharmacology: A Scoping Review of Drug Metabolism in Prematurely Born Children

“…Twenty studies investigating the in vivo phase II metabolism were identified ( Windorfer and Pringsheim, 1977 ; Mulhall et al, 1983a ; Choonara et al, 1989 ; Hartley et al, 1993 , 1994 ; H et al, 1993; Reiter and Stiles, 1993 ; Brammer and Coates, 1994 ; Sato et al, 1997 ; Wenzl et al, 1998 ; Wade et al, 2008 , 2009 ; Knibbe et al, 2009 ; Krekels et al, 2015 ; Mahmood, 2015 ; Auriti et al, 2016 ; Cook et al, 2016 ; Flint et al, 2017 ; MF et al, 2017 ; Leroux et al, 2018 ; Gerhart et al, 2019 ). A large heterogenitet was found and several substrates were used and included chloramphenicol, morphine, fluconazole, lorazepam, micafungin, paracetamol, and mefenamic acid.…”