Pharmacokinetics of fluconazole in the cerebrospinal fluid of children with hydrocephalus

Background: The aim of this study was to examine the pharmacokinetics of fluconazole in the CSF of children with hydrocephalus during CNS infection treatment after intravenous and/or intraventricular drug administration. Direct fluconazole administration into the ventricular CSF of patients to treat serious CNS infections is an aggressive therapy, and data on the pharmacokinetics of fluconazole in CSF are limited. Methods: A method of fluconazole quantification in CSF by solid-phase extraction (SPE)-high-performance liquid chromatography ( HPLC) was developed to conduct pharmacokinetic studies. The population of patients included 2 children with hydrocephalus. Fluconazole was administered intravenously at average multiple doses of 12.5 mg/kg/ 24 h and intraventricularly at doses of 4, 5 and 7.5 mg/24 h, and 7.5 and 10 mg/12 h. The CSF samples were taken 2 - 24 h after administration of fluconazole. The concentrations of fluconazole in CSF specimens were assessed, and after pharmacokinetic studies the fluconazole dosage was modified. Results: The method of fluconazole determination in CSF using the SPE-HPLC method is specific, precise and accurate. After intravenous fluconazole administration, the concentration of this antifungal drug was not detected in the ventricular CSF. The pharmacokinetic parameters determined after intraventricular fluconazole administration were: steady-state peak CSF fluconazole concentration (19.54 +/- 5.63 mg/l); trough CSF fluconazole concentration (0.0 - 0.3 mg/l); elimination rate constant (0.4654 +/- 0.2097 h(-1)), and half-life (1.84 +/- 0.93 h). Conclusions: The authors developed a method to determine fluconazole in CSF by SPE-HPLC. After intravenous fluconazole administration, the drug was not detected in the examined CSF samples. The intraventricular multidose pharmacokinetic data suggest the necessity of fluconazole monitoring in children with hydrocephalus during the treatment of shunt infection. Copyright (C) 2005 S. Karger AG, Basel.