Impact of dose adaptations following voriconazole therapeutic drug monitoring in pediatric patients.


Lempers VJ, Meuwese E, Mavinkurve-Groothuis AM, Henriet S, van der Sluis IM, Hanff LM, Warris A, Koch BCP, Brüggemann RJ.
Med Mycol. 2019 Nov 1;57(8):937-943.


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 hematologiconcology wards were retrospectively identified based on unexplained high voriconazole trough concentrations (Cmin > 6 mg/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 centers. First Cmin (3.1 mg/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 2.16 mg/l (0.0 (undetectable)–28.0), with 24.1% of Cmin < 1 mg/l, 48.9% 1–4 mg/l, 9.3% 4–6 mg/l, and 17.7% > 6 mg/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 and 4 mg/l. Dose decreases at Cmin > 6 mg/l resulted in a decreased Cmin in 80%, with 51% between 1 and 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 1–4 mg/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.

Key words: voriconazole, therapeutic drug monitoring, pediatrics, azoles, pharmacokinetics.