Comparison of Busulfan Pharmacokinetics Between Four-times-daily and Once-daily Administration in Pediatric Patients: a Preliminary Prospective Observational Trial

Overview

Journal Int J Hematol

Specialty Hematology

Date 2024 Dec 3

PMID 39625679

Authors

Atsushi Yamaguchi

Shinsuke Hirabayashi

Kazuko Niki

Keisuke Kagami

Yukayo Terashita

Yuko Cho

Atsushi Manabe

Mitsuru Sugawara

Yoh Takekuma

Affiliations

Soon will be listed here.

Abstract

Therapeutic drug monitoring (TDM) of busulfan (BU) is useful for achieving the target area under the curve (AUC) because its effective plasma-concentration range is narrow. This preliminary observational study evaluated the pharmacokinetic (PK) parameters of BU administered four times daily or once daily to pediatric patients. The plasma concentrations were measured at both the test dose and first dose, and the doses on day 1 and days 2-4 were determined based on each TDM. A comparison of PK parameters between four-times-daily and once-daily administration was performed for both the test dose and first dose of BU. Of the 11 patients, five received four-times-daily BU and six received once-daily BU. The V for once-daily administration was higher than that for four-times-daily administration for the first dose but not for the test dose. The ratio of actual AUC for the first dose to estimated AUC guided by the test dose was lower with once-daily administration than with four-times-daily administration. These results indicate that the PK parameters of BU administered once daily are challenging to predict based on the TDM of the test dose. TDM should be considered on day 1 to achieve the target AUC, especially with once-daily administration.

References

Bartelink I, Lalmohamed A, van Reij E, Dvorak C, Savic R, Zwaveling J . Association of busulfan exposure with survival and toxicity after haemopoietic cell transplantation in children and young adults: a multicentre, retrospective cohort analysis. Lancet Haematol. 2016; 3(11):e526-e536. PMC: 5159247. DOI: 10.1016/S2352-3026(16)30114-4. View

Philippe M, Neely M, Rushing T, Bertrand Y, Bleyzac N, Goutelle S . 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. 2018; 54(3):448-457. DOI: 10.1038/s41409-018-0281-7. View

Versluys A, Boelens J, Pronk C, Lankester A, Bordon V, Buechner J . Hematopoietic cell transplant in pediatric acute myeloid leukemia after similar upfront therapy; a comparison of conditioning regimens. Bone Marrow Transplant. 2021; 56(6):1426-1432. DOI: 10.1038/s41409-020-01201-w. View

Andersson B, Kashyap A, Gian V, Wingard J, Fernandez H, Cagnoni P . Conditioning therapy with intravenous busulfan and cyclophosphamide (IV BuCy2) for hematologic malignancies prior to allogeneic stem cell transplantation: a phase II study. Biol Blood Marrow Transplant. 2002; 8(3):145-54. DOI: 10.1053/bbmt.2002.v8.pm11939604. View

Ryu S, Lee J, Choi S, Lee J, Lee Y, Seol M . Randomized comparison of four-times-daily versus once-daily intravenous busulfan in conditioning therapy for hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2007; 13(9):1095-105. DOI: 10.1016/j.bbmt.2007.06.005. View

Madden T, de Lima M, Thapar N, Nguyen J, Roberson S, Couriel D . Pharmacokinetics of once-daily IV busulfan as part of pretransplantation preparative regimens: a comparison with an every 6-hour dosing schedule. Biol Blood Marrow Transplant. 2007; 13(1):56-64. DOI: 10.1016/j.bbmt.2006.08.037. 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

Zao J, Schechter T, Liu W, Gerges S, Gassas A, Egeler R . Performance of Busulfan Dosing Guidelines for Pediatric Hematopoietic Stem Cell Transplant Conditioning. Biol Blood Marrow Transplant. 2015; 21(8):1471-8. DOI: 10.1016/j.bbmt.2015.05.006. View

Sakashita K, Yoshida N, Muramatsu H, Ohtsuka Y, Watanabe K, Yabe M . Allogeneic Hematopoietic Cell Transplantation for Juvenile Myelomonocytic Leukemia with a Busulfan, Fludarabine, and Melphalan Regimen: JPLSG JMML-11. Transplant Cell Ther. 2023; 30(1):105.e1-105.e10. DOI: 10.1016/j.jtct.2023.10.002. View

10.

McCune J, Quinones C, Ritchie J, Carpenter P, van Maarseveen E, Yeh R . Harmonization of Busulfan Plasma Exposure Unit (BPEU): A Community-Initiated Consensus Statement. Biol Blood Marrow Transplant. 2019; 25(9):1890-1897. PMC: 6755045. DOI: 10.1016/j.bbmt.2019.05.021. View

11.

Harris A, Young R, Devine S, Hogan W, Ayuk F, Bunworasate U . International, Multicenter Standardization of Acute Graft-versus-Host Disease Clinical Data Collection: A Report from the Mount Sinai Acute GVHD International Consortium. Biol Blood Marrow Transplant. 2015; 22(1):4-10. PMC: 4706482. DOI: 10.1016/j.bbmt.2015.09.001. View

12.

Corbacioglu S, Carreras E, Ansari M, Balduzzi A, Cesaro S, Dalle J . Diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in pediatric patients: a new classification from the European society for blood and marrow transplantation. Bone Marrow Transplant. 2017; 53(2):138-145. PMC: 5803572. DOI: 10.1038/bmt.2017.161. View

13.

Schechter T, Finkelstein Y, Doyle J, Verjee Z, Moretti M, Koren G . Pharmacokinetic disposition and clinical outcomes in infants and children receiving intravenous busulfan for allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2007; 13(3):307-14. DOI: 10.1016/j.bbmt.2006.10.026. View

14.

Kim Y, Moon S, Rhee S . Optimal Once-Daily Busulfan Administration in Pediatric Patients: A Simulation-Based Investigation of Intravenous Infusion Times. Drug Des Devel Ther. 2024; 18:871-879. PMC: 10961087. DOI: 10.2147/DDDT.S451970. View

15.

Tse W, Duerst R, Schneiderman J, Chaudhury S, Jacobsohn D, Kletzel M . Age-dependent pharmacokinetic profile of single daily dose i.v. busulfan in children undergoing reduced-intensity conditioning stem cell transplant. Bone Marrow Transplant. 2009; 44(3):145-56. DOI: 10.1038/bmt.2008.437. View

16.

Ohwada C, Yamazaki S, Shono K, Kayamori K, Hino Y, Oshima-Hasegawa N . Pharmacokinetically guided, once-daily intravenous busulfan in combination with fludarabine for elderly AML/MDS patients as a conditioning regimen for allogeneic stem cell transplantation. Int J Hematol. 2021; 114(6):664-673. DOI: 10.1007/s12185-021-03188-6. View

17.

Ward J, Kletzel M, Duerst R, Fuleihan R, Chaudhury S, Schneiderman J . Single Daily Busulfan Dosing for Infants with Nonmalignant Diseases Undergoing Reduced-Intensity Conditioning for Allogeneic Hematopoietic Progenitor Cell Transplantation. Biol Blood Marrow Transplant. 2015; 21(9):1612-21. DOI: 10.1016/j.bbmt.2015.05.017. View

18.

Ludden T . Nonlinear pharmacokinetics: clinical Implications. Clin Pharmacokinet. 1991; 20(6):429-46. DOI: 10.2165/00003088-199120060-00001. View

19.

Hassan M, Oberg G, Ehrsson H, Ehrnebo M, Wallin I, Smedmyr B . Pharmacokinetic and metabolic studies of high-dose busulphan in adults. Eur J Clin Pharmacol. 1989; 36(5):525-30. DOI: 10.1007/BF00558081. View

20.

Ehrsson H, Hassan M . Binding of busulfan to plasma proteins and blood cells. J Pharm Pharmacol. 1984; 36(10):694-6. DOI: 10.1111/j.2042-7158.1984.tb04847.x. View