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Vitamin D levels and busulphan kinetics in patients undergoing hematopoietic stem cell transplantation, a multicenter study

Bone Marrow Transplantation volume 56, pages 807–817 (2021)Cite this article

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Abstract

Vitamin D (Vit-D), an essential nutrient, interacts with different drugs including chemotherapeutic agents like busulphan, an alkylating agent used for conditioning prior to stem cell transplantation. The correlation between Vit-D plasma levels and busulphan clearance was investigated in an uncontrolled prospective study in patients and mice. Plasma 25(OH)D levels were measured and busulphan pharmacokinetics calculated in 81 patients. Adults received oral busulphan (n = 34) while children received busulphan orally (n = 19) or intravenously (n = 28). Patients received no Vit-D supplementation. To confirm our findings, pharmacokinetics after a single dose of busulphan (oral or intravenous) were evaluated in two groups of mice (n = 60) receiving high or standard-level Vit-D supplementation. Both busulphan clearance (P < 0.0001) and 25(OH)D levels (P = 0.0004) were significantly higher in adults compared to children. A significant negative correlation (P = 0.041) was found between busulphan clearance and 25(OH)D levels in children treated orally. No such correlation was observed in adults or in children receiving intravenous busulphan. In addition, no significant effect of Vit-D levels on busulphan pharmacokinetics in mice regardless of the administration route. In conclusion, 25(OH)D can affect oral busulphan pharmacokinetics in children and its level should be considered when personalizing oral busulphan treatment. Further studies are warranted to confirm the underlying mechanisms.

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Fig. 1: Correlation between 25-hydroxyvitamin D levels and busulphan AUCs.
Fig. 2: Correlation between 25-hydroxyvitamin D levels and busulphan clearance.
Fig. 3: Comparison of busulphan AUCs following different administration routes with respect to Vit-D insufficiency.
Fig. 4: Comparison of busulphan clearance following different administration routes with respect to Vit-D insufficiency.
Fig. 5: Busulphan AUCs in the different patient groups.
Fig. 6: Busulphan clearance in the different patient groups.
Fig. 7: 25-hydroxyvitamin D levels in different patient groups.

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Acknowledgements

This study was supported by the Swedish Cancer Society (CAN2014/759), the Swedish Childhood Cancer Foundation (PR2017-0083), KI funds (2018-02377) and (2018-02344), and Radiumhemmets Research Funding (grant no. 161082). The authors would like to express their gratitude to Professor Per Ljungman for his valuable discussions.

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  1. These authors contributed equally: Ahmed El-Serafi, Rui He

Authors and Affiliations

  1. Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden

    Ahmed El-Serafi & Ibrahim El-Serafi

  2. Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Suez Canal University, Ismailia, Egypt

    Ahmed El-Serafi

  3. Experimental Cancer Medicine, Division of Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden

    Rui He, Wenyi Zheng, Fadwa Benkossou, Sandra Oerther, Ying Zhao & Moustapha Hassan

  4. Clinical Research Center and Center of Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital Huddinge, Stockholm, Sweden

    Rui He, Wenyi Zheng, Fadwa Benkossou, Ying Zhao & Moustapha Hassan

  5. Pre-clinical Laboratory, Karolinska University Hospital, Huddinge, Stockholm, Sweden

    Sandra Oerther

  6. Department of Pediatric Oncology, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden

    Karin Mellgren

  7. Department of Clinical Science, Intervention and Technology, CLINTEC, Karolinska Institutet, Stockholm, Sweden

    Britt Gustafsson

  8. Pediatric Clinic, Rigshospitalet, National University Hospital, Copenhagen, Denmark

    Carsten Heilmann

  9. HUS Helsinki University Hospital and University of Helsinki, New Children’s Hospital, Division of Hematology-Oncology and Stem Cell Transplantation, Helsinki, Finland

    Jukka Kanerva

  10. Clinical Pharmacology, Division of Drug Research, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden

    Kourosh Lotfi

  11. Department of Hematology, Linköping University Hospital, Linköping, Sweden

    Kourosh Lotfi

  12. Department of Pediatrics, Skåne University Hospital, Lund, Sweden

    Jacek Toporski

  13. Division of Pediatrics, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden

    Mikael Sundin

  14. Section of Pediatric Hematology, Immunology and HCT, Astrid Lindgren Children’s Hospital, Stockholm, Sweden

    Mikael Sundin

  15. Department of Medical Sciences, Uppsala University, Uppsala, Sweden

    Martin Höglund

  16. Gloria and Seymour Epstein Chair in Cell Therapy and Transplantation, University of Toronto, Toronto, Canada

    Jonas Mattsson

  17. Princess Margaret Cancer Centre, Toronto, ON, Canada

    Jonas Mattsson

  18. Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

    Jonas Mattsson & Ibrahim El-Serafi

  19. Department of Biochemistry, Faculty of Medicine, Port-Said University, Port-Said, Egypt

    Ibrahim El-Serafi

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El-Serafi, A., He, R., Zheng, W. et al. Vitamin D levels and busulphan kinetics in patients undergoing hematopoietic stem cell transplantation, a multicenter study. Bone Marrow Transplant 56, 807–817 (2021). https://doi.org/10.1038/s41409-020-01091-y

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