Pharmacokinetics of Itraconazole Oral Solution in Neutropenic Children during Long-Term Prophylaxis

Abstract

We investigated the pharmacokinetics and safety of an oral solution of itraconazole in two groups of neutropenic children stratified by age. Effective concentrations of itraconazole in plasma were reached quickly and maintained throughout treatment. The results indicate a trend toward higher concentrations of itraconazole in plasma in older children.Invasive fungal infections are frequently observed in neutropenic patients (4). Several antifungal agents are available to treat and prevent invasive mycoses, but poor efficacy and a narrow spectrum of activity can limit their use (4, 17). Itraconazole is a broad-spectrum, orally active, triazole, which has favorable pharmacokinetics and is effective against many mycopathogens, including Candida and Aspergillus species (6, 15). An oral capsule formulation of itraconazole is as effective as intravenous amphotericin B (16), but it must be taken with food to be absorbed effectively. Additionally, children may experience difficulty in swallowing solid drug formulations, so itraconazole capsules are seldom used in children (2).A 10-mg/ml oral solution of itraconazole in combination with hydroxypropyl-␤-cyclodextrin has been developed, which is effective in adults receiving bone marrow autografts (11), adults in remission from acute myeloid leukemia (12), and HIV-positive adult patients with oral candidiasis (8, 10). Furthermore, the itraconazole oral solution prevents fungal infections in neutropenic adults (7, 9). Data regarding itraconazole oral solution in children are limited, although one study showed that it provided potentially therapeutic concentrations (3).Children aged between 2 and 5 years (group 1) or between 6 and 12 years (group 2) were enrolled into this open-label, multicenter trial. All children were hospitalized for chemotherapy and were at risk of invasive fungal infection. Patients were excluded if they had received a bone marrow allograft or whole-body irradiation, had taken an inducer or inhibitor of hepatic metabolism within 2 weeks before the trial, had neutropenia that was expected to last for fewer than 14 days, or had been treated with astemizole, terfenadine, digoxin, or warfarin. The trial protocol was approved by the local ethics committee. Parental consent and, if possible, consent from the children were obtained. The trial was performed in accordance with the declaration of Helsinki and its amendments, and with French law.All patients received itraconazole oral solution (2.5 mg/kg) twice daily. Treatment was started 7 to 10 days before expected onset of neutropenia and was discontinued 2 days after neutropenia had ended or if the investigator felt it clinically necessary to switch to amphotericin B. Itraconazole oral solution was given before breakfast and then 12 h later, before the evening meal. Predose blood samples (4 ml) were taken from an antecubital vein immediately before the morning administration of itraconazole (8 or 9 a.m.) on day 1, then every 2 days until the neutrophil count recovered, and then after a further 2 days. Additio...

Safety, Pharmacokinetics, and Pharmacodynamics of Cyclodextrin Itraconazole in Pediatric Patients with Oropharyngeal Candidiasis

“…Adverse effects tend to be transient and may include gastrointestinal disturbances (Ͻ10%), hypertriglyceridemia (9%), hypokalemia and elevated levels of hepatic transaminases (5% each), and rash or pruritus, headaches or dizziness, and pedal edema (Ͻ2% each) (31). The favorable safety profile of oral CD-ITRA observed in pediatric patients enrolled in our study is consistent with that reported for immunocompromised pediatric patients with cancer or following liver transplantation and receiving the compound at 5 mg/kg QD (7) or 2.5 mg/kg BID (29) for approximately 14 days. These favorable safety data, however, stand somewhat in contrast to those of a third study that evaluated the safety and tolerance of CD-ITRA administered at dosages of 5 mg/kg QD and 2.5 mg/kg BID for a median duration of 37 days for antifungal prophylaxis in children undergoing hematopoietic stem cell transplantation (9).…”

“…In addition, both dosage regimens tested in this study yielded peak and trough drug levels similar to or slightly higher than those reported for immunocompromised adults receiving similar dosage regimens (2,24). In several studies, in comparison to the results for QD dosing, trough levels of ITRA and OH-ITRA were consistently higher after BID dosing with the same total daily dosage (7,24,29). Given the concentration-and time-dependent pharmacodynamics of the antifungal azoles (15), BID dosing thus appears more appropriate, despite the prolonged half-life that by itself would suggest QD dosing.…”

“…In 26 infants and children 6 months to 12 years old, with cancer (n ϭ 20) or undergoing liver transplantation, and receiving CD-ITRA at 5 mg/kg QD (7), plasma drug concentrations were substantially lower than those reported in adult cancer patients (24,25), particularly for infants Ͻ2 years old. However, in a second pharmacokinetic study of children 1.7 to 14.3 years old, with cancer, and receiving CD-ITRA in the form of a split dosing regimen of 2.5 mg/kg BID, peak and trough drug concentrations were similar to or slightly higher than those in adults (29). Nevertheless, there was a similar trend toward less exposure in the group of children Յ5 years old.…”

Posaconazole Plasma Concentrations in Juvenile Patients with Invasive Fungal Infection

“…Results of studies examining the pediatric/juvenile pharmacokinetics of currently marketed azole antifungals, such as itraconazole (7,12,25), fluconazole (3,15,16,26), and voriconazole (29), have been published. Two studies (12,25) with itraconazole show similar peak and trough concentrations for pediatric and adult patients (17 patients, ages 2 to 18 years), and another (7) reports pediatric concentrations that were approximately one-third of those attained by adults (26 patients, ages 6 months to 12 years) (4,7,22,23).…”

“…Although investigation of the pharmacokinetic profile of a drug in children is often delayed during the drug development process, results have been published of studies examining the pharmacokinetics in pediatric patients of currently marketed azole antifungals, such as itraconazole (7,12,25), fluconazole (3,15,16,26), and voriconazole (29). Pharmacokinetic profiles for itraconazole are inconsistent between pediatric patients and adults, and some pharmacokinetic parameters of fluconazole and voriconazole appear to differ between children and adults.…”