Repeated-Dose Pharmacokinetics of an Oral Solution of Itraconazole in Infants and Children

Abstract

ABSTRACT The safety, tolerability, and pharmacokinetics of an oral solution of itraconazole and its active metabolite hydroxyitraconazole were investigated in an open multicenter study of 26 infants and children aged 6 months to 12 years with documented mucosal fungal infections or at risk for the development of invasive fungal disease. The most frequent underlying illness was acute lymphoblastic leukemia, except in the patients aged 6 months to 2 years, of whom six were liver transplant recipients. The patients were treated with itraconazole at a dosage of 5 mg/kg of body weight once daily for 2 weeks. Blood samples were taken after the first dose, during treatment, and up to 8 days after the last itraconazole dose. On day 1, the mean peak concentrations in plasma after the first and last doses ( C max ) and areas under the concentration-time curve from 0 to 24 h (AUC 0–24 ) for itraconazole and hydroxyitraconazole were lower in the children aged 6 months to 2 years than in children aged 2 to 12 years but were comparable on day 14. The mean AUC 0–24 -based accumulation factors of itraconazole and hydroxyitraconazole from day 1 to 14 ranged from 3.3 to 8.6 and 2.3 to 11.4, respectively. After 14 days of treatment, C max , AUC 0–24 , and the half-life, respectively, were (mean ± standard deviation) 571 ± 416 ng/ml, 6,930 ± 5,830 ng · h/ml, and 47 ± 55 h in the children aged 6 months to 2 years; 534 ± 431 ng/ml, 7,330 ± 5,420 ng · h/ml, and 30.6 ± 25.3 h in the children aged 2 to 5 years; and 631 ± 358 ng/ml, 8,770 ± 5,050 ng · h/ml, and 28.3 ± 9.6 h in the children aged 5 to 12 years. There was a tendency to have more frequent low minimum concentrations of the drugs in plasma for both itraconazole and hydroxyitraconazole for the children aged 6 months to 2 years. The oral bioavailability of the solubilizer hydroxypropyl-β-cyclodextrin was less than 1% in the majority of the patients. In conclusion, an itraconazole oral solution given at 5 mg/kg/day provides potentially therapeutic concentrations in plasma, which are, however, substantially lower than those attained in adult cancer patients, and is well tolerated and safe in infants and children.