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A phase I dose finding study of intravenous voriconazole in pediatric patients undergoing hematopoietic cell transplantation

Bone Marrow Transplantation volume 55, pages 955–964 (2020)Cite this article

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Abstract

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.

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Acknowledgements

We would like to acknowledge the assistance of the Clinical Pharmacology Shared Resource of the Masonic Cancer Center, designated by the National Cancer Institute, supported in part by P30 CA77598.

Funding

This work was supported by the Hematology Oncology Pharmacist Association (HOPA) Foundation (MNK), and the Department of Pediatrics, Division of Blood and Marrow Transplant, University of Minnesota (ARS).

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Authors and Affiliations

  1. Department of Pediatrics, Division of Hematology/Oncology/BMT, University of Colorado School of Medicine, Aurora, CO, USA

    Jessica Knight-Perry

  2. Department of Pediatrics, Division of Blood and Marrow Transplant, University of Minnesota School of Medicine, Minneapolis, MN, USA

    Cathryn Jennissen, Susie E. Long, Stefanie Hage, Todd E. DeFor & Angela R. Smith

  3. Department of Experimental and Clinical Pharmacology, University of Minnesota College of Pharmacy, Minneapolis, MN, USA

    Wing T. Chan, James Fisher & Mark N. Kirstein

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  1. Jessica Knight-Perry
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Correspondence to Jessica Knight-Perry.

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Knight-Perry, J., Jennissen, C., Long, S.E. et al. A phase I dose finding study of intravenous voriconazole in pediatric patients undergoing hematopoietic cell transplantation. Bone Marrow Transplant 55, 955–964 (2020). https://doi.org/10.1038/s41409-019-0757-0

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