Voriconazole Therapeutic Drug Monitoring in a Pediatric Hematopoietic Stem Cell Transplant Center

Invasive fungal infections remain one of the most serious complications of hematopoietic stem cell transplantation, occurring in 10-20% of recipients, with mortality rates exceeding 50%. The epidemiology of invasive fungal infections has changed in recent decades requiring changes in drug therapy for both prophylaxis and treatment. Voriconazole, a triazole antifungal with mold coverage, is being used more widely due to this changing epidemiology which has resulted in the need for more frequent therapeutic drug monitoring to evaluate efficacy and safety.

The Infectious Disease Society of America recommends therapeutic drug monitoring of voriconazole secondary to the known wide inter- and intra-patient variability and genetic polymorphisms. It has been previously demonstrated that voriconazole follows linear pharmacokinetics in pediatric patients at doses less than 7 mg/kg, however current increased dosing recommendations exceed this dose. In addition, increased doses may increase the risk of adverse effects including hepatic enzyme alteration and central nervous system effects. These clinical practice changes further advocate for therapeutic drug monitoring.

Pediatric dosing recommendations for voriconazole were recently increased based on the inability to reach therapeutic drug concentrations between the recommended range of 1-6 mCg/mL, particularly in patients less than 2 years of age. Based on these studies and recommendations, dosing strategies at our institution were updated to 9 mg/kg twice daily to a maximum dose of 350 mg in patients less than 12 years of age and 6 mg/kg twice daily to a maximum dose of 400 mg for 2 doses followed by 4 mg/kg twice daily to a maximum dose of 200 mg for patients greater than or equal to 12 years of age. Of the thirteen voriconazole levels collected, 23% were within goal range, 23% were above goal range, and 54% were below goal range. None of the patients experienced hepatic enzyme elevations or central nervous system effects causing discontinuation of voriconazole. The small number of patients within goal range supports the inter- and intra-patient variability previously reported. For this reason, close evaluation of voriconazole levels and genetic polymorphism testing prior to initiation is warranted.