Impact of Dose Adaptations Following Voriconazole Therapeutic Drug Monitoring in Pediatric Patients

Vincent J. Lempers, Edmé Meuwese, Annelies Mavinkurve-Groothuis, Stefanie Henriet, Inge M. van der Sluis, Lidwien M. Hanff, Adilia Warris, Birgit C. P. Koch, Roger J. Brüggemann (Corresponding Author)

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Abstract

Voriconazole is the mainstay of treatment for invasive aspergillosis in immunocompromised pediatric patients. Although Therapeutic Drug Monitoring (TDM) of voriconazole is recommended, it remains unknown if TDM-based dose adaptations result in target attainment. Patients < 19 years from two pediatric hematologic-oncology wards were retrospectively identified based on unexplained high voriconazole trough concentrations (Cmin >6mg/L). Patient demographics, clinical characteristics, treatment, voriconazole dosing information, voriconazole Cmin before and after adjustment based on TDM were obtained. Twenty-one patients, median (range) age 7.0 (1.2-18.5) years, were identified in two centres. First Cmin (3.1mg/L [0.1-13.5]) was obtained after 3 days (1-27) of treatment. The median of all Cmin (n=485, median 11 per patient) was 2.16mg/L (0.0 (undetectable)–28.0), with 24.1% of Cmin <1mg/L, 48.9% 1- 4mg/L, 9.3% 4-6mg/L and 17.7% >6mg/L. Intrapatient variability was large (94.1% for IV, 88.5% for PO). Dose increases at Cmin <1 mg/L resulted in an increased Cmin in 76.4%, with 60% between 1-4 mg/L. Dose decreases at Cmin >6 mg/L resulted in a decreased Cmin in 80%, with 51% between 1-4 mg/L. Overall in 45% of the cases (33 out of 55 and 12 out of 45) therapeutic targets were attained after dose adjustment. Fifty-five percent of initial Cmin was outside the therapeutic target of 1-4mg/L, with multiple dose adaptations required to achieve therapeutic concentrations. Only 60% and 51% of dose adaptations following sub- and supra-therapeutic Cmin, respectively, did result in target attainment. Intensive and continuous TDM of voriconazole is a prerequisite for ensuring adequate exposure in pediatric patients.
Original languageEnglish
JournalMedical Mycology
Early online date13 Feb 2019
DOIs
Publication statusE-pub ahead of print - 13 Feb 2019

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Keywords

  • voriconazole
  • therapeutic drug monitoring
  • pediatrics
  • azoles
  • pharmacokinetics

Cite this

Lempers, V. J., Meuwese, E., Mavinkurve-Groothuis, A., Henriet, S., van der Sluis, I. M., Hanff, L. M., ... Brüggemann, R. J. (2019). Impact of Dose Adaptations Following Voriconazole Therapeutic Drug Monitoring in Pediatric Patients. Medical Mycology. https://doi.org/10.1093/mmy/myz006