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

Abstract

This investigation was designed to evaluate the single-dose pharmacokinetics of itraconazole, hydroxyitraconazole, and hydroxypropyl-␤-cyclodextrin (HP-␤-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-␤-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-␤-CD averaged 1,015 ؎ 692 ng/ml, 293 ؎ 133 ng/ml, and 329 ؎ 200 g/ml, respectively. The total body exposures (area under the concentration-time curve from 0 to 24 h) for itraconazole, hydroxyitraconazole, and HP-␤-CD averaged 4,922 ؎ 6,784 ng ⅐ h/ml, 3,811 ؎ 2,794 ng ⅐ h/ml, and 641.5 ؎ 265.0 g ⅐ 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 (r 2 ‫؍‬ 0.18, P ‫؍‬ 0.02), C max (r 2 ‫؍‬ 0.14, P ‫؍‬ 0.045), and terminal elimination rate (r 2 ‫؍‬ 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.With both traditional and emerging fungal pathogens contributing to an increasing rate of morbidity, invasive mycoses remain a serious and potentially fatal complication for immunocompromised children (1,16,23,26,27,31). In recent years, a growing number of new therapeutic agents have found their way to market (28). However, the management of systemic fungal infections is still restricted to a relatively small number of drug classes encompassing a limited number of pharmacologic actions (i.e., most are cell wall-acting agents). As such, the spectrum of activity and established efficacy, in combination with the pharmacokinetic and toxicity profiles of each agent, will shape their role in therapy.Itraconazole is a first-generation synthetic triazole antifungal that has been in clinical use for nearly two decades. Although fungistatic against pathogenic yeast, itraconazole retains activity against a portion of fluconazole-resistant isolates and demonstrates fungicidal activity against a number of filamentous organisms that cause severe invasive disease (25). Compa...

Pharmacokinetics of Diclofenac and Hydroxypropyl‐β‐Cyclodextrin (HPβCD) Following Administration of Injectable HPβCD‐Diclofenac in Subjects With Mild to Moderate Renal Insufficiency or Mild Hepatic Impairment

“…Using moderate renal insufficiency as the worst case, the exposure to HPβCD after administration of HPβCD‐diclofenac was still estimated to be 7.9‐fold lower based on AUC 0–t and 3.9‐fold lower based on the average concentration than in healthy subjects administered intravenous itraconazole. Notably, the PK profile of HPβCD following administration of intravenous itraconazole has previously been studied in subjects with mild, moderate, and severe renal insufficiency, with results similar to those observed in the present study — a 2.3‐fold decrease in CL and a 3.7‐fold increase in t ½ were observed for subjects with mild or moderate renal insufficiency, whereas a 6‐fold decrease in CL and a 6‐fold increase in t ½ were observed for subjects with severe renal insufficiency versus healthy subjects 33, 34…”

Diagnosis and Initial Management of Musculoskeletal Coccidioidomycosis in Children

“…system, and as a result, the pharmacokinetics profile is highly variable 73 . Routine monitoring of serum drug levels is recommended, especially in cases of concomitant treatment with other medications with which there may be a drug interaction 69,74 .…”

Efficacy and safety of itraconazole use in infants

“…[10] However, the single-dose pharmacokinetics of ITR and hydroxyitraconazole after intravenous administration to children was evaluated, and no relationship was found between age and maximum plasma concentrations or total body clearance. [11] Repeated-dose pharmacokinetics of ITR-OS at a dose of 5 mg/kg per day for 2 weeks in infants and children showed that the potentially therapeutic plasma concentrations were lower in infants aged 6 months to 2 years than those in children aged 2 to 12 years on day 1, but comparable on day 14. The study also indicated that severe infections might need higher doses.…”