Open AccessA phase I dose finding study of intravenous voriconazole in pediatric patients undergoing hematopoietic cell transplantation
Author(s) -
Jessica KnightPerry,
Cathryn Jennissen,
Susie Long,
Stefanie M Hage,
Todd E. DeFor,
Wing T. Chan,
James E. Fisher,
Mark N. Kirstein,
Angela R. Smith
Publication year - 2019
Publication title -
bone marrow transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.609
H-Index - 127
eISSN - 1476-5365
pISSN - 0268-3369
DOI - 10.1038/s41409-019-0757-0
Subject(s) - medicine , voriconazole , dosing , pharmacokinetics , gastroenterology , transplantation , hematopoietic stem cell transplantation , therapeutic drug monitoring , toxicity , population , pharmacology , antifungal , dermatology , environmental health
To optimize voriconazole dosing in pediatric hematopoietic cell transplantation (HCT), we conducted a phase I study with a modified 3 + 3 dose-escalation followed by an expansion cohort at the maximum tolerated, minimum efficacious dose (MTD/MED). Patients ≤21 years who required voriconazole for prevention or treatment of an invasive fungal infection were assigned to three age groups. Of the 59 evaluable patients, 13 were <2 years, 23 were 2-11, and 23 were 12-21. Therapeutic serum voriconazole troughs (1.5-5 µg/mL) drawn at 7 days after initiation determined efficacy. The MTD/MED was 12 mg/kg/dose q12 h × 2 loading doses, then 10 mg/kg/dose q12 h in patients <2, and was 10 mg/kg/dose q12 h in patients 2-11. The 12-21 age group had no dose-limiting toxicity at 8 mg/kg/dose q12 h; however, the MED was not reached. Drug-related AEs ≥grade 3 included increased bilirubin, transaminases, and creatinine, all occurring in <10%. There was no significant association between supra-therapeutic troughs and AEs. Five of 17 patients who had supra-therapeutic troughs (29%) had an AE, compared to 8 of 42 who did not (19%, p = 0.38). Observational population pharmacokinetic analysis demonstrated that inter-individual variability on voriconazole clearance was >100% CV, and clearance increased with age.