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

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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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 (2020). https://doi.org/10.1038/s41409-020-01091-y

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