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Antimicrobial Agents and Chemotherapy, August 2007, p. 2668-2673, Vol. 51, No. 8
0066-4804/07/$08.00+0     doi:10.1128/AAC.00297-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Single-Dose Pharmacokinetics of Intravenous Itraconazole and Hydroxypropyl-ß-Cyclodextrin in Infants, Children, and Adolescents

Division of Pediatric Clinical Pharmacology and Medical Toxicology, The Children's Mercy Hospital,¹ Department of Pediatrics, University of Missouri-Kansas City, Kansas City, Missouri,² Section of Infectious Diseases, Arkansas Children's Hospital, Little Rock, Arkansas,³ Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Raritan, New Jersey,⁴ Section of Infectious Diseases, Children's Hospital-San Diego, San Diego, California,⁵ Division of Pediatric Pharmacology and Critical Care, Rainbow Babies and Children's Hospital,⁶ Departments of Pediatrics and Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio⁷

Received 1 March 2007/ Returned for modification 9 April 2007/ Accepted 13 May 2007

This investigation was designed to evaluate the single-dose pharmacokinetics of itraconazole, hydroxyitraconazole, and hydroxypropyl-ß-cyclodextrin (HP-ß-CD) after intravenous administration to children at risk for fungal infection. Thirty-three children aged 7 months to 17 years received a single dose of itraconazole (2.5 mg/kg in 0.1-g/kg HP-ß-CD) administered over 1 h by intravenous infusion. Plasma samples for the determination of the analytes of interest were drawn over 120 h and analyzed by high-pressure liquid chromatography, and the pharmacokinetics were determined by traditional noncompartmental analysis. Consistent with the role of CYP3A4 in the biotransformation of itraconazole, a substantial degree of variability was observed in the pharmacokinetics of this drug after IV administration. The maximum plasma concentrations (C_max) for itraconazole, hydroxyitraconazole, and HP-ß-CD averaged 1,015 ± 692 ng/ml, 293 ± 133 ng/ml, and 329 ± 200 µg/ml, respectively. The total body exposures (area under the concentration-time curve from 0 to 24 h) for itraconazole, hydroxyitraconazole, and HP-ß-CD averaged 4,922 ± 6,784 ng·h/ml, 3,811 ± 2,794 ng·h/ml, and 641.5 ± 265.0 µg·h/ml, respectively, with no significant age dependence observed among the children evaluated. Similarly, there was no relationship between age and total body clearance (702.8 ± 499.4 ml/h/kg); however, weak associations between age and the itraconazole distribution volume (r² = 0.18, P = 0.02), C_max (r² = 0.14, P = 0.045), and terminal elimination rate (r² = 0.26, P < 0.01) were noted. Itraconazole infusion appeared to be well tolerated in this population with a single adverse event (stinging at the site of infusion) deemed to be related to study drug administration. Based on the findings of this investigation, it appears that intravenous itraconazole can be administered to infants beyond 6 months, children, and adolescents using a weight-normalized approach to dosing.

Published ahead of print on 21 May 2007.