Importance of voriconazole therapeutic drug monitoring in pediatric cancer patients with invasive aspergillosis

Background: Voriconazole is the drug of choice for invasive aspergillosis (IA) and drug levels are influenced by interactions with other drugs and genetic predisposition. We performed a retrospective analysis of voriconazole drug levels and investigated the adequacy of drug levels in pediatric cancer patients and hematopoietic cell transplant (HCT) recipients with IA. Procedure: Trough serum concentrations of voriconazole in patients younger than 19 years during a 30-month period were analyzed. The therapeutic range was determined as 1-6μg/ml. Results: A total of 193 voriconazole measurements at steady-state [86 on intravenous (IV) and 107 on oral (PO) doses] were obtained from 27 patients (median age 12.2 years). On the first monitoring, 19 patients (70.4%) achieved the therapeutic range. However, only 10 patients (37.0%) achieved the therapeutic range on second monitoring. Sixty-four percent of the total measurements were within the therapeutic range: 66.3% of IV and 61.7% of PO. A significant correlation between oral doses and trough levels of voriconazole was observed in patients ≤6 years old (Spearman's rank correlation coefficient=0.4819, P=0.027). Patients aged ≤6 years needed a significantly higher median dose of PO voriconazole to maintain therapeutic trough levels compared to older patient groups (8.9 vs. 4.2mg/kg/dose, P<0.001). Voriconazole level <1μg/ml was more frequently observed in patients with treatment failure at week 6 of voriconazole therapy (failure vs. success, 42.1% vs. 19.7%; P=0.012). Conclusions: Serum concentrations of voriconazole in children were variable, depending on the patient's age and route of administration. Continuous and careful drug level monitoring should be performed.