title: Population Pharmacokinetics of Fluconazole in Premature Infants with Birth Weights Less than 750 Grams.
abstract: Fluconazole is an effective agent for prophylaxis of invasive candidiasis in premature infants. The objective of this study was to characterize the population pharmacokinetics (PK) and dosing requirements of fluconazole in infants with birth weights of <750 g. As part of a randomized clinical trial, infants born at <750 g birth weight received intravenous (i.v.) or oral fluconazole at 6 mg/kg of body weight twice weekly. Fluconazole plasma concentrations from samples obtained by either scheduled or scavenged sampling were measured using a liquid chromatography-tandem mass spectrometry assay. Population PK analysis was conducted using NONMEM 7.2. Population PK parameters were allometrically scaled by body weight. Covariates were evaluated by univariable screening followed by multivariable assessment. Fluconazole exposures were simulated in premature infants using the final PK model. A population PK model was developed from 141 infants using 604 plasma samples. Plasma fluconazole PK were best described by a one-compartment model with first-order elimination. Only serum creatinine was an independent predictor for clearance in the final model. The typical population parameter estimate for oral bioavailability in the final model was 99.5%. Scavenged samples did not bias the parameter estimates and were as informative as scheduled samples. Simulations indicated that the study dose maintained fluconazole troughs of >2,000 ng/ml in 80% of simulated infants at week 1 and 59% at week 4 of treatment. Developmental changes in fluconazole clearance are best predicted by serum creatinine in this population. A twice-weekly dose of 6 mg/kg achieves appropriate levels for prevention of invasive candidiasis in extremely premature infants.
authors.affiliation: University of California, San Diego, La Jolla, California, USA.
authors.forename: Jeremiah D
authors.initials: JD
authors.lastname: Momper
authors.affiliation: University of California, San Diego, La Jolla, California, USA.
authors.forename: Edmund V
authors.initials: EV
authors.lastname: Capparelli
authors.affiliation: Children's Hospital of Philadelphia, Pennsylvania, USA.
authors.forename: Kelly C
authors.initials: KC
authors.lastname: Wade
authors.affiliation: Children's Hospital Medical Center of Akron, Akron, Ohio, USA.
authors.forename: Anand
authors.initials: A
authors.lastname: Kantak
authors.affiliation: University of Tennessee Health System, Memphis, Tennessee, USA.
authors.forename: Ramasubbareddy
authors.initials: R
authors.lastname: Dhanireddy
authors.affiliation: East Carolina University, Brody School of Medicine, Greenville, North Carolina, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Cummings
authors.affiliation: Cook Children's Medical Center, Fort Worth, Texas, USA.
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Nedrelow
authors.affiliation: University of Florida College of Medicine, Jacksonville, Florida, USA.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Hudak
authors.affiliation: Kings County Hospital, Brooklyn, New York, USA.
authors.forename: Gratias T
authors.initials: GT
authors.lastname: Mundakel
authors.affiliation: Wayne State University, Detroit, Michigan, USA.
authors.forename: Girija
authors.initials: G
authors.lastname: Natarajan
authors.affiliation: Duke Clinical Research Institute, Durham, North Carolina, USA.
authors.forename: Jamie
authors.initials: J
authors.lastname: Gao
authors.affiliation: Duke Clinical Research Institute, Durham, North Carolina, USA.
authors.forename: Matt
authors.initials: M
authors.lastname: Laughon
authors.affiliation: Duke University Medical Center, Durham, North Carolina, USA Duke Clinical Research Institute, Durham, North Carolina, USA brian.smith@duke.edu.
authors.forename: P Brian
authors.initials: PB
authors.lastname: Smith
authors.affiliation: Duke University Medical Center, Durham, North Carolina, USA Duke Clinical Research Institute, Durham, North Carolina, USA.
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Benjamin
mesh_terms: D000935:Antifungal Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001724:Birth Weight / Q000187:drug effects*; D005260:Female; D015725:Fluconazole / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007234:Infant, Premature; D008297:Male
chemical_list: D000935:Antifungal Agents; D015725:Fluconazole