title: Highly variable plasma concentrations of voriconazole in pediatric hematopoietic stem cell transplantation patients.
abstract: Invasive fungal infections are of great concern in pediatric hematopoietic stem cell transplantation (HSCT) recipients. Voriconazole is usually the drug of first choice for treating or preventing invasive aspergillosis. Optimum trough levels (C(trough)s) are between 1 and 5 mg/liter. It is unclear whether these levels are reached with currently advised pediatric dosing schedules. Between 2007 and 2011, 11 patients <2 years of age, 31 between 2 and 12 years, and 20 between 12 and 20 years were (prophylactically or therapeutically) treated with voriconazole in the HSCT unit of UMC Utrecht. For children <2 years of age, the dosage recommended for 2 to 12 years was used. In 34% of children who started with the recommended dose, an adequate C(trough) was reached irrespective of age or administration route. After therapeutic drug monitoring (TDM)-based dose adjustments, adequate C(trough)s were reached in 80% of the patients at median doses of 31.5 (age, <2 years), 16 (age, 2 to 12 years), and 9.4 mg/kg of body weight/day (age, >12 years) (P = 0.034). The intrapatient variability in C(trough) ranged between 1 and 238%. Voriconazole was discontinued in six patients due to toxicity. These patients had a median C(trough) of 0.5 mg/liter at the initial dose (ranging from 0.5 to 2.6 mg/liter), and a medium maximal concentration of 4 mg/liter was reached. Inter- and intrapatient variability is a major concern in voriconazole treatment and necessitates therapeutic drug monitoring of dosing, especially in young children.
authors.affiliation: Pediatric Blood and Marrow Transplantation Program, UMC Utrecht, Utrecht, Netherlands. i.h.bartelink@gmail.com
authors.forename: Imke H
authors.initials: IH
authors.lastname: Bartelink
authors.forename: Tom
authors.initials: T
authors.lastname: Wolfs
authors.forename: Martine
authors.initials: M
authors.lastname: Jonker
authors.forename: Marjolein
authors.initials: M
authors.lastname: de Waal
authors.forename: Toine C G
authors.initials: TC
authors.lastname: Egberts
authors.forename: Tessa T
authors.initials: TT
authors.lastname: Ververs
authors.forename: Jaap J
authors.initials: JJ
authors.lastname: Boelens
authors.forename: Marc
authors.initials: M
authors.lastname: Bierings
mesh_terms: D000293:Adolescent; D000704:Analysis of Variance; D000935:Antifungal Agents / Q000097:blood* / Q000493:pharmacokinetics / Q000494:pharmacology; D001228:Aspergillosis / Q000097:blood* / Q000188:drug therapy / Q000382:microbiology / Q000517:prevention & control; D001230:Aspergillus / Q000187:drug effects / Q000254:growth & development; D002648:Child; D002675:Child, Preschool; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D016903:Drug Monitoring; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D008297:Male; D011743:Pyrimidines / Q000097:blood* / Q000493:pharmacokinetics / Q000494:pharmacology; D016896:Treatment Outcome; D014230:Triazoles / Q000097:blood* / Q000493:pharmacokinetics / Q000494:pharmacology; D065819:Voriconazole; D055815:Young Adult
chemical_list: D000935:Antifungal Agents; D011743:Pyrimidines; D014230:Triazoles; D065819:Voriconazole