Pharmacokinetics and safety of intravenous voriconazole in children after single- or multiple-dose administration

Abstract

We conducted a multicenter study of the safety, tolerability, and plasma pharmacokinetics of the parenteral formulation of voriconazole in immunocompromised pediatric patients (2 to 11 years old). Single doses of 3 or 4 mg/kg of body weight were administered to six and five children, respectively. In the multiple-dose study, 28 patients received loading doses of 6 mg/kg every 12 h on day 1, followed by 3 mg/kg every 12 h on day 2 to day 4 and 4 mg/kg every 12 h on day 4 to day 8. Standard population pharmacokinetic approaches and generalized additive modeling were used to construct the structural pharmacokinetic and covariate models used in this analysis. In contrast to that in adult healthy volunteers, elimination of voriconazole was linear in children following doses of 3 and 4 mg/kg every 12 h. Body weight was more influential than age in accounting for the observed variability in voriconazole pharmacokinetics. Elimination capacity correlated with the CYP2C19 genotype. Exposures were similar at 4 mg/kg every 12 h in children (median area under the concentration-time curve (AUC), 14,227 ng. h/ml) and 3 mg/kg in adults (median AUC, 13,855 ng. h/ml). Visual disturbances occurred in 5 (12.8%) of the 39 patients and were the only drug-related adverse events that occurred more than once. No withdrawals from the study were related to voriconazole. We conclude that pediatric patients have a higher capacity for elimination of voriconazole per kilogram of body weight than do adult healthy volunteers and that dosages of 4 mg/kg may be required in children to achieve exposures consistent with those in adults following dosages of 3 mg/kg.

FIG. 1.

Concentration-time curve of voriconazole after multiple-dose administration in subjects aged from 2 to 5 years and from 6 to 11 years. Voriconazole was given i.v. in doses of 3 (solid lines) and 4 (dashed lines) mg/kg every 12 h. The samples were collected on day 4 of each dosing regimen. The points represent means, and the error bars represent standard deviations. BL, baseline.

FIG. 2.

Individual concentration-time curves of voriconazole in immunocompromised children aged from 2 to 5 and from 6 to 11 years. Each line represents an individual subject. The solid lines with diamonds demonstrate geometric mean concentrations.