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/microl) 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 (C(max)), the area under the plasma concentration-time curve (AUC) from 0 to 24 h (AUC(0-24)), the concentration in plasma at the end of the dosing interval (predose) (C(min)), and the terminal half-life of itraconazole (ITRA) were (means and standard deviations) 0.604 +/- 0.53 microg/ml, 6.80 +/- 7.4 microg. h/ml, 0.192 +/- 0.06 microg/ml, and 56.48 +/- 44 h, respectively, for the QD regimen and 1.340 +/- 0.75 microg/ml, 23.04 +/- 14.5 microg. h/ml, 0.782 +/- 0.19 microg/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 < 0.05). The OPC score (range, 0 to 13) for all 26 patients decreased from a mean of 7.46 +/- 0.8 at baseline to 2.8 +/- 0.7 at the end of therapy (P < 0.001), demonstrating antifungal efficacy in this setting. The relationships among C(max), C(min), AUC(0-12), C(max)/MIC, C(min)/MIC, AUC(0-12)/MIC, time during the dosing interval when the plasma drug concentrations were above the MIC for the infecting isolate, and the residual OPC score at day 15 for the entire study population fit inhibitory effect pharmacodynamic models (r, 0.595 to 0.421; P, <0.01 to <0.05). All patients with fluconazole-resistant isolates responded to treatment with CD-ITRA; however, there was no clear correlation between the MIC of ITRA and response to therapy. In conclusion, CD-ITRA was well tolerated and efficacious for the treatment of OPC in HIV-infected pediatric patients. Pharmacodynamic modeling revealed significant correlations between plasma drug concentrations and antifungal efficacy. Based on this documented safety and efficacy, a dosage of 2.5 mg/kg BID can be recommended for the treatment of OPC in pediatric patients > or =5 years old.