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Pretransplant Conditioning in Adults and Children: Dose Assurance With Intravenous Busulfan

Vicki L. Fisher
Yvonne J. Barnes
Suzanne L. Nuss
ONF 2006, 33(2), E36-E43 DOI: 10.1188/06.ONF.E36-E43

Purpose/Objectives: To provide clinical insights into dosing and administration of IV busulfan, a conditioning agent for hematopoietic stem cell transplantation (HSCT).

Data Sources: Review of published literature related to busulfan pretransplant conditioning using MEDLINE®. Meeting abstracts, investigational protocols, and pharmaceutical manufacturers' package inserts also were reviewed.

Data Synthesis: Busulfan is an effective myeloablative conditioning agent for HSCT. The IV formulation increases dose assurance and the ability to target a therapeutic window. Therapeutic drug monitoring ensures that targeted blood levels are achieved, especially in children, thereby preventing underdosing, which can lead to disease progression or rejection, as well as overdosing, which can cause an increased risk of toxic side effects.

Conclusions: IV busulfan is a convenient, safe, and effective conditioning agent used in HSCT that has a predictable pharmacokinetic profile.

Implications for Nursing: An understanding of the pharmacokinetic principles underlying the relationship between the therapeutic window for busulfan and optimal HSCT outcomes will facilitate proper dosing and administration of IV busulfan.

References 

Afify, Z., Shaw, P.J., Clavano-Harding, A., & Cowell, C.T. (2000). Growth and endocrine function in children with acute myeloid leukaemia after bone marrow transplantation using busulfan/cyclophosphamide. <i>Bone Marrow Transplantation, 25</i>, 1087-1092.

Andersson, B.S., Thall, P.F., Madden, T., Couriel, D., Wang, X., Tran, H.T., et al. (2002). 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. <i>Biology of Blood and Marrow Transplantation, 8</i>, 477-485.

Bearman, S.I. (2001). Avoiding hepatic veno-occlusive disease: What do we know and where are we going? <i>Bone Marrow Transplantation, 27</i>, 1113-1120.

Bolinger, A.M., Zangwill, A.B., Slattery, J.T., Risler, L.J., Sultan, D.H., Glidden, D.V., et al. (2001). Target dose adjustment of busulfan in pediatric patients undergoing bone marrow transplantation. <i>Bone Marrow Transplantation, 11</i>, 1013-1018.

Chou, R.H., Wong, G.B., Kramer, J.H., Wara, D.W., Matthay, K.K., Crittenden, M.R., et al. (1996). Toxicities of total-body irradiation for pediatric bone marrow transplantation. <i>International Journal of Radiation Oncology, Biology, Physics, 34</i>, 843-851.

Cohen, A., Rovelli, A., Van-Lint, M.T., Uderzo, C., Morchio, A., Pezzini, C., et al. (1996). Final height of patients who underwent bone marrow transplantation during childhood. <i>Archives of Disease in Childhood, 74</i>, 437-440.

Dix, S.P., Wingard, J.R., Mullins, R.E., Jerkunica, I., Davidson, T.G., Gilmore, C.E., et al. (1996). Association of busulfan area under the curve with veno-occlusive disease following BMT. <i>Bone Marrow Transplantation, 17</i>, 225-230.

Dupuis, L.L., Najdova, M., & Saunders, E.F. (2000). Retrospective appraisal of busulfan dose adjustment in children. <i>Bone Marrow Transplantation, 26</i>, 1143-1147.

ESP Pharma, Inc. (2003). IV Busulfex® (busulfan) injection. Complete prescribing information. Edison, NJ: Author.

Giorgiani, G., Bozzola, M., Locatelli, F., Picco, P., Zecca, M., Cisternino, M., et al. (1995). Role of busulfan and total body irradiation on growth of prepubertal children receiving bone marrow transplantation and results of treatment with recombinant human growth hormone. <i>Blood, 86</i>, 825-831.

Grochow, L.B. (1993). Busulfan disposition: The role of therapeutic monitoring in bone marrow transplantation induction regimens. <i>Seminars in Oncology, 20</i>(4, Suppl. 4), 18-25.

Grochow, L.B. (2002). Parenteral busulfan: Is therapeutic monitoring still warranted? <i>Biology of Blood and Marrow Transplantation, 8</i>, 465-467.

Grochow, L.B., Jones, R.J., Brundrett, R.B., Braine, H.G., Chen, T.L., Saral, R., et al. (1989). Pharmacokinetics of busulfan: Correlation with veno-occlusive disease in patients undergoing bone marrow transplantation. <i>Cancer Chemotherapy and Pharmacology, 25</i>, 55-61.

Grochow, L.B., Krivit, W., Whitley, C.B., & Blazar, B. (1990). Busulfan disposition in children. <i>Blood, 75</i>, 1723-1727.

Hassan, M., Ehrsson, H., & Ljungman, P. (1996). Aspects concerning busulfan pharmacokinetics and bioavailability. <i>Leukemia and Lymphoma, 22</i>, 395-407.

Hassan, M., Ljungman, P., Bolme, P., Ringden, O., Syruckova, Z., Bekassy, A., et al. (1994). Busulfan bioavailability. <i>Blood, 84</i>, 2144-2150.

Hassan, M., Oberg, G., Bekassy, A.N., Aschan, J., Ehrsson, H., Ljungman, P., et al. (1991). Pharmacokinetics of high-dose busulphan in relation to age and chronopharmacology. <i>Cancer Chemotherapy and Pharmacology, 28</i>, 130-134.

Hassan, M., Oberg, G., Ehrsson, H., Ehrnebo, M., Wallin, I., Smedmyr, B., et al. (1989). Pharmacokinetics and metabolic studies of high-dose busulphan in adults. <i>European Journal of Clinical Pharmacology, 36</i>, 525-530.

Kashyap, A., Wingard, J., Cagnoni, P., Roy, J., Tarantolo, S., Hu, W., et al. (2002). IV versus oral busulfan as part of a busulfan/cyclophosphamide preparative regimen for allogeneic hematopoietic stem cell transplantation: Decreased incidence of hepatic venoocclusive disease (HVOD), HVOD-related mortality, and overall 100-day mortality. <i>Biology of Blood and Marrow Transplantation, 8</i>, 493-500.

Lindley, C., Shea, T., McCune, J., Shord, S., Decker, J., Harvey, D., et al. (2004). Intraindividual variability in busulfan pharmacokinetics in patients undergoing a bone marrow transplant: Assessment of a test dose and first dose strategy. <i>Anticancer Drugs, 15</i>, 453-459.

Ljungman, P., Hassan, M., Bekassy, A.N., Ringden, O., & Oberg, G. (1997). High busulfan concentrations are associated with increased transplant-related mortality in allogeneic bone marrow transplant patients. <i>Bone Marrow Transplantation, 20</i>, 909-913.

McCune, J.S., Gibbs, J.P., & Slattery, J.T. (2000). Plasma concentration monitoring of busulfan: Does it improve clinical outcome? <i>Clinical Pharmacokinetics, 39</i>, 155-165.

McCune, J.S., Gooley, T., Gibbs, J.P., Sanders, J.E., Petersdorf, E.W., Appelbaum, F.R., et al. (2002). Busulfan concentration and graft rejection in pediatric patients undergoing hematopoietic stem cell transplantation. <i>Bone Marrow Transplantation, 30</i>, 167-173.

Meresse, V., Hartmann, O., Vassal, G., Benhamou, E., Valteau-Couanet, D., Brugieres, L., et al. (1992). Risk factors for hepatic veno-occlusive disease after high-dose busulfan-containing regimens followed by autologous bone marrow transplantation: A study in 136 children. <i>Bone Marrow Transplantation, 10</i>, 135-141.

Puozzo, C., Fuller, D., Nguyen, L., & Lennon, S. (2003). A novel dosing to improve safety/efficacy of a IV Bu/Cy regimen in children (PEDS) undergoing haematopoietic progenitor cell transplantation (HPCT) [Abstract 3252]. <i>Proceedings of the American Society of Clinical Oncology, 22</i>, 809.

Russell, J.A., Tran, H.T., Quinlan, D., Chaudhry, A., Duggan, P., Brown, C., et al. (2002). Once-daily intravenous busulfan given with fludarabine as conditioning for allogeneic stem cell transplantation: Study of pharmacokinetics and early clinical outcomes. <i>Biology of Blood and Marrow Transplantation, 8</i>, 468-476.

Santos, G.W., Tutschka, P.J., Brookmeyer, R., Saral, R., Beschorner, W.E., Bias, W.B., et al. (1983). Marrow transplantation for acute nonlymphocytic leukemia after treatment with busulfan and cyclophosphamide. <i>New England Journal of Medicine, 309</i>, 1347-1353.

Schuler, U., Schroer, S., Kuhnle, A., Blanz, J., Mewes, K., Kumbier, I., et al. (1994). Busulfan pharmacokinetics in bone marrow transplant patients: Is drug monitoring warranted? <i>Bone Marrow Transplantation, 14</i>, 759-765.

Slattery, J.T., Sanders, J.E., Buckner, C.D., Schaffer, R.L., Lambert, K.W., Langer, F.P., et al. (1995). Graft-rejection and toxicity following bone marrow transplantation in relation to busulfan pharmacokinetics. <i>Bone Marrow Transplantation, 16</i>, 31-42.

Tran, H.T., Madden, T., Petropoulos, D., Worth, L.L., Felix, E.A., Sprigg-Saenz, H.A., et al. (2000). Individualizing high-dose oral busulfan: Prospective dose adjustment in a pediatric population undergoing allogeneic stem cell transplantation for advanced hematologic malignancies. <i>Bone Marrow Transplantation, 26</i>, 463-470.

Vassal, G. (1994). Pharmacologically-guided dose adjustment of busulfan in high-dose chemotherapy regimens: Rationale and pitfalls [Review]. <i>Anticancer Research, 14</i>, 2363-2370.

Vassal, G., Challine, D., Koscielny, S., Hartmann, O., Deroussent, A., Boland, I., et al. (1993). Chronopharmacology of high-dose busulfan in children. <i>Cancer Research, 53</i>, 1534-1537.

Vassal, G., Deroussent, A., Hartmann, O., Challine, D., Benhamou, E., Valteau-Couanet, D., et al. (1990). Dose-dependent neurotoxicity of high-dose busulfan in children: A clinical and pharmacological study. <i>Cancer Research, 50</i>, 6203-6207.

Vassal, G., Gouyette, A., Hartmann, O., Pico, J.L., & Lemerle, J. (1989). Pharmacokinetics of high-dose busulfan in children. <i>Cancer Chemotherapy and Pharmacology, 24</i>, 386-390.

Wall, D., Chang, K.W., Nieder, M., Feingold, J., Hayashi, R., Yeager, A., et al. (2000). Phase II trial of intravenous busulfan (Busulfex®) with cyclophosphamide in pediatric allogeneic stem cell transplantation: Pharmacokinetics, toxicity and efficacy (A Pediatric Blood and Marrow Transplant Consortium Study) [Abstract 2066]. <i>Blood, 96</i>(Suppl. 1), 480a.