title: Safety and pharmacokinetics of fluconazole in children with neoplastic diseases.
abstract: To evaluate the safety, tolerance, and pharmacokinetics of fluconazole in children with neoplastic diseases, we studied fluconazole in 26 children, aged 5 to 15 years, with normal renal function who were receiving treatment for cancer. The patients received fluconazole, 2, 4, or 8 mg/kg per day for 7 days intravenously for a 2-hour period. Patients had no nausea or vomiting related to fluconazole; three patients had an asymptomatic rise in hepatic aminotransferase values after four to six doses (one patient at 2 mg/kg per day and two patients at 8 mg/kg per day), which returned to normal within 2 weeks after discontinuation of the drug. Fluconazole showed linear first-order kinetics over the dosage range tested and during multiple dosing. After the first dose, mean clearance was 22.8 +/- 2.3 ml/min, volume of distribution 0.87 +/- 0.06 L/kg, and terminal elimination half-life 16.8 +/- 1.1 hours. Similarly, after the last dose, clearance was 19.4 +/- 1.3 ml/min, volume of distribution 0.84 +/- 0.04 L/kg, and terminal elimination half-life 18.1 +/- 1.2 hours. Patients receiving their first fluconazole dose of 8 mg/kg achieved peak serum levels of 9.5 +/- 0.4 microgram/ml and trough levels of 2.7 +/- 0.5 microgram/ml 24 hours later, and an area under the serum concentration-time curve from time zero to infinity of 186 +/- 16 micrograms.hr per milliliter. Renal clearance of fluconazole was 65% +/- 5% of total clearance and demonstrated the predominantly renal excretion of this drug. We suggest that the shorter serum half-life and the higher frequency of aminotransferase elevations in comparison with those of adults warrant careful investigation of fluconazole in controlled clinical trials.
authors.affiliation: Infectious Diseases Section, National Cancer Institute, Bethesda, MD 20892.
authors.forename: J W
authors.initials: JW
authors.lastname: Lee
authors.forename: N L
authors.initials: NL
authors.lastname: Seibel
authors.forename: M
authors.initials: M
authors.lastname: Amantea
authors.forename: P
authors.initials: P
authors.lastname: Whitcomb
authors.forename: P A
authors.initials: PA
authors.lastname: Pizzo
authors.forename: T J
authors.initials: TJ
authors.lastname: Walsh
mesh_terms: D002648:Child; D004334:Drug Administration Schedule; D004341:Drug Evaluation; D005260:Female; D015725:Fluconazole / Q000493:pharmacokinetics* / Q000633:toxicity*; D006801:Humans; D007668:Kidney / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008111:Liver Function Tests; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism*; D012983:Soft Tissue Neoplasms / Q000378:metabolism*
chemical_list: D015725:Fluconazole