Monitoring Plasma Voriconazole Levels May Prevent Subtheraputic Dosing in Pediatrics Hematopoeitic Stem Cell Transplantation (HCT)

Background: Voriconazole is frequently used for prophylaxis and treatment of fungal infections during hematopoeitic stem cell transplant (HCT). Clinical studies demonstrate a poorer outcome when voriconazole concentrations are < 0.5 mcg/ml. Pediatric dosing schedules to achieve trough concentrations > 0.5 mcg/ml are not established and the recommended dose based on adult data is 4mg/kg/ dose q12h. Methods: Retrospective analysis of voriconazole trough levels in 53 pediatric patients following allogeneic HCT receiving fungal prophylaxis with oral or IV voriconazole. Ages ranged 0.5 to 20 years, median 14 years. Serum levels were measured by high-performance liquid chromatography. Samples were obtained 5 to 7 days after start or change in dose of voriconazole, 298 total levels were evaluated. Results: The mean age of patients with levels < 0.5 mcg/ml was 6.4 years and 13 years for those with levels > 0.5mcg/ml. Most patients failing to achieve adequate trough levels were < 9 years of age (15/17 patients). A level of > 0.5mcg/ml was achievable in a subset of these patients (8/15) when the dosage was increased from 4mg/kg/dose q 12h to doses ranging from 6mg to 11 mg /kg/dose q12h. 7/15 never achieved a level > 0.5mcg/ml despite doses ranging from 7 to 8.2mg/ kg/dose. 2/17 patients that were < 9 years of age did achieve a level > 0.5mcg/ml with dosing of 4mg/kg/dose. Changing from oral to IV therapy in 3 patients with low trough levels did not improve the trough level. Multi-time point measurements were > 0.5mcg/ml at 2 to 6 hours after oral / IV dose, but fell to 0.2mcg/ml by 12 hours in 3 patients tested. Of 298 voriconazole levels, 156 were > 0.5 mcg/ml. Conclusions: Unlike reports in adult patients, we found that frequent monitoring of voriconazole levels was necessary in pediatric patients less than 10 years old receiving HCT. In addition, younger pediatric HCT patients may require more frequent dosing schedules to achieve trough levels or initial dosing higher than the recommended adult dosing of 4mg/kg/dose q12h.