Comparison of pharmacokinetics and safety of voriconazole intravenous-to-oral switch in immunocompromised children and healthy adults.

Driscoll TA, Yu LC, Frangoul H, Krance RA, Nemecek E, Blumer J, Arrieta A, Graham ML, Bradfield SM, Baruch A, Liu P
Antimicrob Agents Chemother. 2011 55 (12): 5770-9

PMID: 21968355 · PMCID: PMC3232783 · DOI:10.1128/AAC.00531-11

Voriconazole pharmacokinetics are not well characterized in children despite prior studies. To assess the appropriate pediatric dosing, a study was conducted in 40 immunocompromised children aged 2 to <12 years to evaluate the pharmacokinetics and safety of voriconazole following intravenous (IV)-to-oral (PO) switch regimens based on a previous population pharmacokinetic modeling: 7 mg/kg IV every 12 h (q12h) and 200 mg PO q12h. Area under the curve over the 12-h dosing interval (AUC(0-12)) was calculated using the noncompartmental method and compared to that for adults receiving approved dosing regimens (6 → 4 mg/kg IV q12h, 200 mg PO q12h). On average, the AUC(0-12) in children receiving 7 mg/kg IV q12h on day 1 and at IV steady state were 7.85 and 21.4 μg · h/ml, respectively, and approximately 44% and 40% lower, respectively, than those for adults at 6 → 4 mg/kg IV q12h. Large intersubject variability was observed. At steady state during oral treatment (200 mg q12h), children had higher average exposure than adults, with much larger intersubject variability. The exposure achieved with oral dosing in children tended to decrease as weight and age increased. The most common treatment-related adverse events were transient elevated liver function tests. No clear threshold of voriconazole exposure was identified that would predict the occurrence of treatment-related hepatic events. Overall, voriconazole IV doses higher than 7 mg/kg are needed in children to closely match adult exposures, and a weight-based oral dose may be more appropriate for children than a fixed dose. Safety of voriconazole in children was consistent with the known safety profile of voriconazole.

MeSH Terms (22)

Administration, Oral Adolescent Adult Antifungal Agents Aryl Hydrocarbon Hydroxylases Child Child, Preschool Cytochrome P-450 CYP2C19 Dose-Response Relationship, Drug Female Genotype Humans Immunocompromised Host Infusions, Intravenous Liver Function Tests Male Middle Aged Pyrimidines Treatment Outcome Triazoles Voriconazole Young Adult

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