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Maximal concentration of intravenous busulfan as a determinant of veno-occlusive disease: a pharmacokinetic-pharmacodynamic analysis in 293 hematopoietic stem cell transplanted children

Bone Marrow Transplantation volume 54, pages 448–457 (2019)Cite this article

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Abstract

Veno-occlusive disease (VOD) is a severe adverse reaction to busulfan-containing regimens used in the preparation of children for hematopoietic stem cell transplantation (HSCT). We conducted a retrospective analysis of data to examine determinants of VOD in children who received IV busulfan for HSCT conditioning. Busulfan PK parameters as well as various indices (maximal concentration—Cmax, area under the concentration-time curve—AUC) were estimated using a validated Bayesian approach. The influence of available PK, demographic, and clinical variables on the incidence of VOD was evaluated by using logistic regression and classification and regression tree (CART) analyses. Among the 293 patients included, the mean age was 6.5 years and the mean actual body weight was 26.3 kg. The incidence of VOD was 25.6%. Busulfan Cmax as well as weight <9 kg or age <3 years were identified as independent predictors of VOD in logistic regression analysis. CART analysis identified busulfan Cmax over the entire regimen as the strongest predictor of VOD. This study suggests that busulfan-associated VOD is in part a concentration-dependent reaction. In addition, the youngest children showed the highest risk of VOD. These findings may have important implications for busulfan dosing and therapeutic drug monitoring practice in HSCT children.

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Acknowledgements

MP, SG, MN, and NB designed the research study. MP and TR collected the data. MP, SG, and TR analyzed the data. MP and SG wrote the paper. TR, MN, and NB critically revised the manuscript. All authors approved the final version of the manuscript.

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Authors and Affiliations

  1. Institute of Pediatric Hematology and Oncology, Lyon, France

    Michaël Philippe & Yves Bertrand

  2. Laboratoire de Biométrie et Biologie Evolutive, UMR CNRS 5558, Université Lyon 1, Villeurbanne, France

    Michaël Philippe & Sylvain Goutelle

  3. Laboratory of Applied Pharmacokinetics and Bioinformatics, Division of Pediatric Infectious Diseases, University of Southern California Children’s Hospital Los Angeles, Los Angeles, USA

    Michael Neely

  4. Pharmacy Department, University of Southern California Children’s Hospital Los Angeles, Los Angeles, USA

    Teresa Rushing

  5. Pharmacotoxicologie, Hospices Civils de Lyon, Lyon, France

    Nathalie Bleyzac

  6. EMR 3738 PK/PD Modeling in Oncology and Hematology, Lyon, France

    Nathalie Bleyzac

  7. Université Lyon 1, ISPB—Faculté de Pharmacie de Lyon, Lyon, France

    Sylvain Goutelle

  8. Service Pharmaceutique, Groupement Hospitalier de Gériatrie, Hospices Civils de Lyon, Lyon, France

    Sylvain Goutelle

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Correspondence to Michaël Philippe.

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Philippe, M., Neely, M., Rushing, T. et al. Maximal concentration of intravenous busulfan as a determinant of veno-occlusive disease: a pharmacokinetic-pharmacodynamic analysis in 293 hematopoietic stem cell transplanted children. Bone Marrow Transplant 54, 448–457 (2019). https://doi.org/10.1038/s41409-018-0281-7

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