Voriconazole pharmacokinetics and safety in immunocompromised children compared to adult patients

Abstract

The aim of this study was to investigate the pharmacokinetics and safety of voriconazole after intravenous (i.v.) administration in immunocompromised children (2 to 11 years old) and adults (20 to 60 years old) who required treatment for the prevention or therapy of systemic fungal infections. Nine pediatric patients were treated with a dose of 7 mg/kg i.v. every 12 h for a period of 10 days. Three children and 12 adults received two loading doses of 6 mg/kg i.v. every 12 h, followed by a maintenance dose of 5 mg/kg (children) or 4 mg/kg (adults) twice a day during the entire study period. Trough voriconazole levels in blood over 10 days of therapy and regular voriconazole levels in blood for up to 12 h postdose on day 3 were examined. Wide intra- and interindividual variations in plasma voriconazole levels were noted in each dose group and were most pronounced in the children receiving the 7-mg/kg dose. Five (56%) of them frequently had trough voriconazole levels in plasma below 1 microg/ml or above 6 microg/ml. The recommended dose of 7 mg/kg i.v. in children provides exposure (area under the concentration-time curve) comparable to that observed in adults receiving 4 mg/kg i.v. The children had significantly higher C(max) values; other pharmacokinetic parameters were not significantly different from those of adults. Voriconazole exhibits nonlinear pharmacokinetics in the majority of children. Voriconazole therapy was safe and well tolerated in pediatric and adult patients. The European Medicines Agency-approved i.v. dose of 7 mg/kg can be recommended for children aged 2 to <12 years.

FIG. 1.

Geometric mean trough concentrations of VRC in plasma of children and adults over 10 days of therapy.

FIG. 2.

Box plot of VRC trough levels in 24 patients over 10 days of therapy (thick bar, median level; box, interquartile range; whiskers, minimum and maximum levels; dot, outlier).

FIG. 3.

Individual and geometric mean concentration-time profiles of VRC in plasma of children and adults on day 3.

FIG. 4.

Individual dose-normalized AUCs (AUC_{0-12 h}/dose) of VRC in children receiving 5 and 7 mg/kg i.v. and dose-normalized median AUCs in children receiving 3 and 4 mg/kg i.v. (*, data from reference ; +, dose-normalized median AUC in children receiving 7 mg/kg i.v.).