Voriconazole (VCZ) Dosing in Pediatric Patients

Background: Voriconazole (VCZ) is a broad spectrum azole antifungal agent and is frequently used for fungal prophylaxis in immunocompromised pediatric patients. Area under the curve (AUC) to minimum inhibitory concentration (MIC) ratio has been used as the pharmacokinetic/pharmacodynamic parameter of efficacy, although single trough measurements above 1 mg/L have been associated with survival benefit. Appropriate dosing to achieve desired VCZ serum concentrations in pediatric patients has been challenging due to variables including bioavailability and rate of metabolism. 

Methods: A single-center, retrospective, cohort analysis was conducted to evaluate patients achieving therapeutic VCZ trough levels with the initial dose over a 15 month period. Secondary endpoints included proportion of patients requiring IV to PO dose adjustments, hepatotoxicity, and percentage of patients with clinical failure of VCZ. Parameters such as age, weight, body surface area, gender, ethnicity, liver function, and selected co-administered medications were collected. Patients with at least one serum VCZ trough level were included in the study.

Results: Between 9/1/11-12/31/12, 3 patients < 1 year of age (Group A), 10 between 1 and 12 years (Group B), and 11 between 12 and 19 years (Group C) were treated with VCZ. Median VCZ dose in group A was 6.1 mg/kg [range 3.7-6.6], group B was 7.4 mg/kg [range 6.5-9.4] and group C was 4 mg/kg [range 3.1-5.5]. There was no significant difference between median doses of patients with and without therapeutic levels (5.4 mg/kg and 5.9 mg/kg, respectively). Of the 3 patients > 10 converted from IV to PO, all needed increased doses to achieve therapeutic VCZ levels. Patient age significantly influenced VCZ levels; weight and height approached significance as influencing factors. One patient had persistent elevation of liver function tests (LFTs) while on VCZ therapy. Despite documented therapeutic VCZ troughs, two therapeutic failures of VCZ therapy were observed. 

Conclusion: Patient age has a significant impact on VCZ trough levels. Patients > 1 year and < 12 years of age required higher weight-based doses to achieve therapeutic levels. Forty-two percent of patients experienced transient elevations in LFTs while on VCZ therapy.