REPEATED-DOSE PHARMACOKINETICS OF AN ORAL SOLUTION OF ITRACONAZOLE ININFANTS AND CHILDREN

The safety, tolerability, and pharmacokinetics of an oral solution of itraconazole and its active metabolite hydroxyitraconazole were invest igated in an open multicenter study of 26 infants and children aged 6 months to 12 years with documented mucosal fungal infections or at ris k for the development of invasive fungal disease, The most frequent un derlying illness was acute lymphoblastic leukemia, except in the patie nts aged 6 months to 2 years, of whom six were liver transplant recipi ents, 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 aft er the first dose, during treatment, and up to 8 days after the last i traconazole dose, On day 1, the mean peak concentrations in plasma aft er 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 hydroxyitra conazole were lower in the children aged 6 months to 2 years than in c hildren aged 2 to 12 years but were comparable on day 14. The mean AUC (0-24)-based accumulation factors of itraconazole and hydroxyitraconaz ole from day 1 to 14 ranged from 3.3 to 8.6 and 2.3 to 11.4, respectiv ely. 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 t o 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 year s, There was a tendency to have more frequent low minimum concentratio ns of the drugs in plasma for both itraconazole and hydroxyitraconazol e for the children aged 6 months to 2 years, The oral bioavailability of the solubilizer hydroxypropyl-beta-cyclodextrin was less than 1% in the majority of the patients, In conclusion, an itraconazole oral sol ution given at 5 mg/kg/day provides potentially therapeutic concentrat ions in plasma, which are, however, substantially lower than those att ained in adult cancer patients, and is well tolerated and safe in infa nts and children.