Vitamin D Levels and Busulphan Kinetics in Patients Undergoing Hematopoietic Stem Cell Transplantation, a Multicenter Study

Overview

Journal Bone Marrow Transplant

Specialty General Surgery

Date 2020 Oct 22

PMID 33087877

Authors

Ahmed El-Serafi

Rui He

Wenyi Zheng

Fadwa Benkossou

Sandra Oerther

Ying Zhao

Karin Mellgren

Britt Gustafsson

Carsten Heilmann

Jukka Kanerva

Kourosh Lotfi

Jacek Toporski

Mikael Sundin

Martin Hoglund

Jonas Mattsson

Ibrahim El-Serafi

Moustapha Hassan

Affiliations

Soon will be listed here.

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.

References

Grochow L . Busulfan disposition: the role of therapeutic monitoring in bone marrow transplantation induction regimens. Semin Oncol. 1993; 20(4 Suppl 4):18-25; quiz 26. View

Andersson B, Thall P, Madden T, Couriel D, Wang X, Tran H . Busulfan systemic exposure relative to regimen-related toxicity and acute graft-versus-host disease: defining a therapeutic window for i.v. BuCy2 in chronic myelogenous leukemia. Biol Blood Marrow Transplant. 2002; 8(9):477-85. DOI: 10.1053/bbmt.2002.v8.pm12374452. View

Slattery J, Risler L . Therapeutic monitoring of busulfan in hematopoietic stem cell transplantation. Ther Drug Monit. 1998; 20(5):543-9. DOI: 10.1097/00007691-199810000-00017. View

Palmer J, McCune J, Perales M, Marks D, Bubalo J, Mohty M . Personalizing Busulfan-Based Conditioning: Considerations from the American Society for Blood and Marrow Transplantation Practice Guidelines Committee. Biol Blood Marrow Transplant. 2016; 22(11):1915-1925. DOI: 10.1016/j.bbmt.2016.07.013. View

Beumer J, Owzar K, Lewis L, Jiang C, Holleran J, Christner S . Effect of age on the pharmacokinetics of busulfan in patients undergoing hematopoietic cell transplantation; an alliance study (CALGB 10503, 19808, and 100103). Cancer Chemother Pharmacol. 2014; 74(5):927-38. PMC: 4210372. DOI: 10.1007/s00280-014-2571-0. View

Ten Brink M, van Bavel T, Swen J, der Straaten T, Bredius R, Lankester A . Effect of genetic variants GSTA1 and CYP39A1 and age on busulfan clearance in pediatric patients undergoing hematopoietic stem cell transplantation. Pharmacogenomics. 2013; 14(14):1683-90. DOI: 10.2217/pgs.13.159. View

Buggia I, Zecca M, Alessandrino E, Locatelli F, Rosti G, Bosi A . Itraconazole can increase systemic exposure to busulfan in patients given bone marrow transplantation. GITMO (Gruppo Italiano Trapianto di Midollo Osseo). Anticancer Res. 1996; 16(4A):2083-8. View

El-Serafi I, Terelius Y, Abedi-Valugerdi M, Naughton S, Saghafian M, Moshfegh A . Flavin-containing monooxygenase 3 (FMO3) role in busulphan metabolic pathway. PLoS One. 2017; 12(11):e0187294. PMC: 5679629. DOI: 10.1371/journal.pone.0187294. View

Hassan M, Svensson J, Nilsson C, Hentschke P, Al-Shurbaji A, Aschan J . Ketobemidone may alter busulfan pharmacokinetics during high-dose therapy. Ther Drug Monit. 2000; 22(4):383-5. DOI: 10.1097/00007691-200008000-00003. View

10.

Bikle D . Vitamin D metabolism, mechanism of action, and clinical applications. Chem Biol. 2014; 21(3):319-29. PMC: 3968073. DOI: 10.1016/j.chembiol.2013.12.016. View

11.

Ross A, Manson J, Abrams S, Aloia J, Brannon P, Clinton S . The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab. 2010; 96(1):53-8. PMC: 3046611. DOI: 10.1210/jc.2010-2704. View

12.

Webb A, Kline L, Holick M . Influence of season and latitude on the cutaneous synthesis of vitamin D3: exposure to winter sunlight in Boston and Edmonton will not promote vitamin D3 synthesis in human skin. J Clin Endocrinol Metab. 1988; 67(2):373-8. DOI: 10.1210/jcem-67-2-373. View

13.

Cheng J, Levine M, Bell N, Mangelsdorf D, Russell D . Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase. Proc Natl Acad Sci U S A. 2004; 101(20):7711-5. PMC: 419671. DOI: 10.1073/pnas.0402490101. View

14.

Holick M . Vitamin D deficiency. N Engl J Med. 2007; 357(3):266-81. DOI: 10.1056/NEJMra070553. View

15.

Parise R, Egorin M, Kanterewicz B, Taimi M, Petkovich M, Lew A . CYP24, the enzyme that catabolizes the antiproliferative agent vitamin D, is increased in lung cancer. Int J Cancer. 2006; 119(8):1819-28. DOI: 10.1002/ijc.22058. View

16.

Holick M, Siris E, Binkley N, Beard M, Khan A, Katzer J . Prevalence of Vitamin D inadequacy among postmenopausal North American women receiving osteoporosis therapy. J Clin Endocrinol Metab. 2005; 90(6):3215-24. DOI: 10.1210/jc.2004-2364. View

17.

Holick M, Binkley N, Bischoff-Ferrari H, Gordon C, Hanley D, Heaney R . Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011; 96(7):1911-30. DOI: 10.1210/jc.2011-0385. View

18.

Ng K, Nimeiri H, McCleary N, Abrams T, Yurgelun M, Cleary J . Effect of High-Dose vs Standard-Dose Vitamin D3 Supplementation on Progression-Free Survival Among Patients With Advanced or Metastatic Colorectal Cancer: The SUNSHINE Randomized Clinical Trial. JAMA. 2019; 321(14):1370-1379. PMC: 6459117. DOI: 10.1001/jama.2019.2402. View

19.

Chae Y, Cho K, Yoon I, Noh C, Lee H, Park Y . Vitamin D Receptor-Mediated Upregulation of CYP3A4 and MDR1 by Quercetin in Caco-2 cells. Planta Med. 2015; 82(1-2):121-30. DOI: 10.1055/s-0035-1557898. View

20.

Wang Z, Schuetz E, Xu Y, Thummel K . Interplay between vitamin D and the drug metabolizing enzyme CYP3A4. J Steroid Biochem Mol Biol. 2012; 136:54-8. PMC: 3549031. DOI: 10.1016/j.jsbmb.2012.09.012. View