Microbiology Spectrum (Apr 2022)

Fluconazole Population Pharmacokinetics after Fosfluconazole Administration and Dosing Optimization in Extremely Low-Birth-Weight Infants

  • Ayano Tanzawa,
  • Jumpei Saito,
  • Kensuke Shoji,
  • Yuka Kojo,
  • Takanori Funaki,
  • Hidehiko Maruyama,
  • Tetsuya Isayama,
  • Yushi Ito,
  • Hidefumi Nakamura,
  • Akimasa Yamatani

DOI
https://doi.org/10.1128/spectrum.01952-21
Journal volume & issue
Vol. 10, no. 2

Abstract

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ABSTRACT A prospective single-center study was conducted to characterize the pharmacokinetics (PK) of fluconazole (FLCZ) in extremely low-birth-weight infants (ELBWIs) who received fosfluconazole (F-FLCZ). Intravenous F-FLCZ was administered at a dose of 3 mg/kg of body weight every 72 h during the first 2 weeks of life, every 48 h during the third and fourth weeks of life, and every 24 h after 5 weeks of life. Blood samples from ELBWIs treated with F-FLCZ were collected using scavenged samples. The concentration of FLCZ was determined using liquid chromatography-tandem mass spectrometry. The population pharmacokinetic model was established using Phenix NLME 8.2 software. In total, 18 ELBWIs were included in this analysis. Individual PK parameters were determined by a one-compartment analysis with first-order conversion. Postmenstrual age (PMA), serum creatinine (SCr), and alkaline phosphatase were considered covariates for clearance (CL). The mean population CL and the volume of distribution were 0.011 L/h/kg0.75 and 0.95 L/kg, respectively. Simulation assessments with the final model revealed that the current regimen (3 mg/kg every 72 h) could achieve the proposed target FLCZ trough concentration (>2 μg/mL) in 43.3% and 72.2% of infants with a PMA of ≥37 and 30 to 36 weeks, respectively, and an SCr level of 10%, under the guidelines of the Infectious Diseases Society of America. Fosfluconazole can reduce the volume of solution required for intravenous therapy compared to fluconazole because it has increased solubility, which is a major advantage for infants undergoing strict fluid management. To date, no study has demonstrated the fluconazole pharmacokinetics after fosfluconazole administration in neonates and infants, and this needs to be clarified. Here, we characterized the pharmacokinetics of fluconazole in extremely low-birth-weight infants who received F-FLCZ and explored the appropriate dosage in this patient population.

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