Monitoring of voriconazole plasma concentrations in immunocompromised paediatric patients.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Infectious Disease Research Program, Centre for Bone Marrow Transplantation and Department of Pediatric Hematology/Oncology,  University Children's Hospital Münster, Münster,  Federal Republic of Germany.
Stephanie
S
Pieper
Hedwig
H
Kolve
Hans G
HG
Gumbinger
Grazyna
G
Goletz
Gudrun
G
Würthwein
Andreas H
AH
Groll
D061605:Administration, Intravenous; D000284:Administration, Oral; D000293:Adolescent; D000935:Antifungal Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D007223:Infant; D008297:Male; D010949:Plasma / Q000737:chemistry*; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D012189:Retrospective Studies; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D065819:Voriconazole
D000935:Antifungal Agents; D011743:Pyrimidines; D014230:Triazoles; D065819:Voriconazole