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

The safety, pharmacokinetics, and pharmacodynamics of cyclodextrin itraconazole (CD-ITRA) oral suspension were investigated in an open sequential dose escalation study with 26 human immunodeficiency virus (HIV)-infected children and adolescents (5 to 18 years old; mean CD4-cell count, 128/l) with oropharyngeal candidiasis (OPC). Patients received CD-ITRA at either 2.5 mg/kg of body weight once a day (QD) or 2.5 mg/kg twice a day (BID) for a total of 15 days. Pharmacokinetic sampling was performed after the first dose and for up to 120 h after the last dose, and antifungal efficacy was evaluated by standardized scoring of the oropharynx. Apart from mild to moderate gastrointestinal disturbances in three patients (11.5%), CD-ITRA was well tolerated. Two patients (7.6%) discontinued treatment prematurely due to study drug-related adverse events. After 15 days of treatment, the peak concentration of drug in plasma (Cmax), the area under the plasma concentration-time curve (AUC) from 0 to 24 h (AUC0‐24), the concentration in plasma at the end of the dosing interval (predose) (Cmin), and the terminal half-life of itraconazole (ITRA) were (means and standard deviations) 0.604 0.53 g/ml, 6.80 7.4 g h/ml, 0.192 0.06 g/ml, and 56.48 44 h, respectively, for the QD regimen and 1.340 0.75 g/ml, 23.04 14.5 g h/ml, 0.782 0.19 g/ml, and 104.22 94 h, respectively, for the BID regimen. The mean AUC-based accumulation factors for ITRA on day 15 were 4.14 0.9 and 3.53 0.6, respectively. A comparison of the dose-normalized median AUC of the two dosage regimens revealed a trend toward nonlinear drug disposition (P 0.05). The mean metabolic ratios (AUC of hydroxyitraconazole/AUC of ITRA) at day 15 were 1.96 0.1 for the QD regimen and 1.29 0.2 for the BID regimen, respectively (P 5 years old.