Monitoring of voriconazole plasma concentrations in immunocompromised paediatric patients

Abstract

Voriconazole is approved for management of invasive fungal diseases (IFDs) in paediatric patients. We analysed plasma trough concentrations and explored their association with endpoints of antifungal therapy. The cohort included 74 immunocompromised patients (0.2-18 years of age) who received 101 courses of voriconazole for possible (7) and probable/proven (13) IFDs, as prophylaxis (79) or empirical therapy (2). Voriconazole was given intravenously (4), intravenously and orally (15) and orally (82) at recommended dosages until intolerance or maximum efficacy. IFDs and outcomes were assessed by EORTC/MSG consensus criteria. Voriconazole was administered at a median maintenance dosage of 4.8 mg/kg twice daily (range 2.2-17.4) for a median of 40 days (range 6-1002). Trough plasma concentrations at steady state (251 samples; 3.4 ± 4.3/patient) ranged from <0.2 to 14.9 mg/L with high intra- and inter-individual variability and no apparent relationship to dose (P = 0.074, ANOVA). Of the samples 22%, 42% and 58% had voriconazole concentrations <0.2, ≤0.5 and ≤1.0 mg/L, respectively. Adverse events (AEs) occurred in 77/101 (76.2%) courses and were mostly grade I or II. Ten courses (9.9%) were discontinued due to AEs. Treatment success was observed in 8/20 patients (40%) with IFDs, and in 67/81 courses (82.7%) of empirical therapy/prophylaxis. There were no consistent correlations between dose, trough concentrations and laboratory/clinical AEs or treatment response, and proposed threshold values were not discriminative. Voriconazole had acceptable safety and useful efficacy in the management of paediatric IFDs. Pharmacokinetic variability was high and no predictable dose-concentration-effect relationships were observed.