Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Conditioning Regimens

Population pharmacokinetics of intravenous busulfan in patients undergoing hematopoietic stem cell transplantation

Bone Marrow Transplantation volume 37, pages 345–351 (2006)Cite this article

Abstract

A population pharmacokinetic analysis was performed in 30 patients who received an intravenous busulfan and cyclophosphamide regimen before hematopoietic stem cell transplantation. Each patient received 0.8 mg/kg as a 2 h infusion every 6 h for 16 doses. A total of 690 concentration measurements were analyzed using the nonlinear mixed effect model (NONMEM) program. A one-compartment model with an additive error model as an intraindividual variability including an interoccasion variability (IOV) in clearance (CL) was sufficient to describe the concentration–time profile of busulfan. Actual body weight (ABW) was found to be the determinant for CL and the volume of distribution (V) according to NONMEM analysis. In this limited study, the age (range 7–53 years old; median, 30 years old) had no significant effect on busulfan pharmacokinetics. For a patient weighting 60 kg, the typical CL and V were estimated to be 8.87 l/h and 33.8 l, respectively. The interindividual variability of CL and V were 13.6 and 6.3%, respectively. The IOV (6.6%) in CL was estimated to be less than the intraindividual variability. These results indicate high interpatient and intrapatient consistency of busulfan pharmacokinetics after intravenous administration, which may eliminate the requirement for pharmacokinetic monitoring.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Santos GW, Tutschka PJ, Brookmeyer R, Saral R, Beschorner WE, Bias WB et al. Marrow transplantation for acute nonlymphocytic leukemia after treatment with busulfan and cyclophosphamide. N Engl J Med 1983; 309: 1347–1353.

    Article  CAS  PubMed  Google Scholar 

  2. Tutschka PJ, Copelan EK, Klein JP . Bone marrow transplantation for leukemia following a new busulfan and cyclophosphamide regimen. Blood 1987; 70: 1382–1388.

    CAS  PubMed  Google Scholar 

  3. Grochow LB, Jones RJ, Brundrett RB, Braine HG, Chen TL, Saral R et al. Pharmacokinetics of busulfan: correlation with veno-occlusive disease in patients undergoing bone marrow transplantation. Cancer Chemother Pharmacol 1989; 25: 55–61.

    Article  CAS  PubMed  Google Scholar 

  4. Dix SP, Wingard JR, Mullins RE, Jerkunica I, Davidson TG, Gilmore CE et al. Association of busulfan area under the curve with veno-occlusive disease following BMT. Bone Marrow Transplant 1996; 17: 225–230.

    CAS  PubMed  Google Scholar 

  5. Hassan M, Oberg G, Bekassy AN, Aschan J, Ehrsson H, Ljungman P et al. Pharmacokinetics of high-dose busulphan in relation to age and chronopharmacology. Cancer Chemother Pharmacol 1991; 28: 130–134.

    Article  CAS  PubMed  Google Scholar 

  6. Slattery JT, Sanders JE, Buckner CD, Schaffer RL, Lambert KW, Langer FP et al. Graft-rejection and toxicity following bone marrow transplantation in relation to busulfan pharmacokinetics. Bone Marrow Transplant 1995; 16: 31–42.

    CAS  PubMed  Google Scholar 

  7. Vassal G, Challine D, Koscielny S, Hartmann O, Deroussent A, Boland I et al. Chronopharmacology of high-dose busulfan in children. Cancer Res 1993; 53: 1534–1537.

    CAS  PubMed  Google Scholar 

  8. Gibbs JP, Gooley T, Corneau B, Murray G, Stewart P, Appelbaum FR et al. The impact of obesity and disease on busulfan oral clearance in adults. Blood 1999; 93: 4436–4440.

    CAS  PubMed  Google Scholar 

  9. Gibbs JP, Murray G, Risler L, Chien JY, Dev R, Slattery JT . Age-dependent tetrahydrothiophenium ion formulation in young children and adults receiving high-dose busulfan. Cancer Res 1997; 57: 5509–5516.

    CAS  PubMed  Google Scholar 

  10. Olavarria E, Hassan M, Eades A, Nilsson C, Timms A, Matthews J et al. A phase I/II study of multiple-dose intravenous busulfan as myeloablation prior to stem cell transplantation. Leukemia 2000; 14: 1954–1959.

    Article  CAS  PubMed  Google Scholar 

  11. Andersson BS, Madden T, Tran HT, Hu WW, Blume KG, Chow DS et al. Acute safety and pharmacokinetics of intravenous busulfan when used with oral busulfan and cyclophosphamide as pretransplantation conditioning therapy: a phase I study. Biol Blood Marrow Transplant 2000; 6: 548–554.

    Article  CAS  PubMed  Google Scholar 

  12. Andersson BS, Kashyap A, Gian V, Wingard JR, Fernandez H, Cagnoni PJ et al. 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: 145–154.

    Article  CAS  PubMed  Google Scholar 

  13. Nguyen L, Fuller D, Lennon S, Leger F, Puozzo C . I.V. busulfan in pediatrics: a novel dosing to improve safety/efficacy for hematopoietic progenitor cell transplantation recipients. Bone Marrow Transplant 2004; 33: 979–987.

    Article  CAS  PubMed  Google Scholar 

  14. Vassal G, Re M, Gouyette A . Gas chromatographic-mass spectrometric assay for busulfan in biological fluids using a deuterated internal standard. J Chromatogr 1988; 428: 357–361.

    Article  CAS  PubMed  Google Scholar 

  15. Ette EI . Stability and performance of a population pharmacokinetic model. J Clin Pharmacol 1997; 37: 486–495.

    Article  CAS  PubMed  Google Scholar 

  16. Efron B . Bootstrap methods: another look at the jackknife. Ann Stat 1979; 7: 1–26.

    Article  Google Scholar 

  17. Karlsson MO, Sheiner LB . The importance of modeling interoccasion variability in population pharmacokinetic analyses. J Pharmacokinet Biopharm 1993; 21: 735–750.

    Article  CAS  PubMed  Google Scholar 

  18. Jonsson EN, Karlsson MO . Xpose – an S-PLUS based population pharmacokinetic/pharmacodynamic model building aid for NONMEM. Comput Meth Prog Biomed 1999; 58: 51–64.

    Article  CAS  Google Scholar 

  19. Hastie TJ . Generalized additive models. In: Chambers JM, Hastie TJ (eds) Statistical models in S. Pacific Grove. CA: Wadsworth & Books/Cole Advanced Books & Software, 1992, pp. 249–307.

    Google Scholar 

  20. Sandström M, Karlsson MO, Ljungman P, Hassan Z, Jonsson EN, Nilsson C et al. Population pharmacokinetic analysis resulting in a tool for dose individualization of busulphan in bone marrow transplantation recipients. Bone Marrow Transplant 2001; 28: 657–664.

    Article  PubMed  Google Scholar 

  21. Schiltmeyer B, Klingebiel T, Schwab M, Murdter TE, Ritter CA, Jenke A et al. Population pharmacokinetics of oral busulfan in children. Cancer Chemother Pharmacol 2003; 52: 209–216.

    Article  CAS  PubMed  Google Scholar 

  22. Aarons L, Balant LP, Mentré F, Morselli PL, Rowland M, Steimer JL et al. Practical experience and issues in designing and performing population pharmacokinetic/pharmacodynamic studies. Eur J Clin Pharmacol 1996; 49: 251–254.

    Article  CAS  PubMed  Google Scholar 

  23. Hoffer E, Akria L, Tabak A, Scherb I, Rowe JM, Krivoy N . A simple approximation for busulfan dose adjustment in adult patients undergoing bone marrow transplantation. Ther Drug Monit 2004; 26: 331–335.

    Article  CAS  PubMed  Google Scholar 

  24. Grochow LB . Busulfan disposition: the role of therapeutic monitoring in bone marrow transplantation induction regimens. Semin Oncol 1993; 20 (Suppl. 4): 18–25.

    CAS  PubMed  Google Scholar 

  25. Andersson BS, Thall PF, Madden T, Couriel D, Wang X, Tran HT et al. Busulfan systemic exposure relative to regimen-related toxicity and acute graft-versus-host disease: defining a therapeutic window for IV BuCy2 in chronic myelogenous leukemia. Biol Blood Marrow Transplant 2002; 8: 477–485.

    Article  CAS  PubMed  Google Scholar 

  26. Hassan M, Fasth A, Gerritsen B, Haraldsson A, Syruckova Z, van den Berg H et al. Busulphan kinetics and limited sampling model in children with leukemia and inherited disorders. Bone Marrow Transplant 1996; 18: 843–850.

    CAS  PubMed  Google Scholar 

  27. Slattery JT . Re: intravenous versus oral busulfan – perhaps not as different as suggested. Biol Blood Marrow Transplantation 2003; 9: 282–284.

    Google Scholar 

  28. Andersson BS, Kashyap A, Couriel D, Madden T, de Lima M, Thall PF et al. Intravenous busulfan in pretransplant chemotherapy: bioavailability and patient benefit. Biol Blood Marrow Transplantation 2003; 9: 722–724.

    Article  Google Scholar 

Download references

Acknowledgements

We are indebted to Professor Hiroyasu Ogata of Meiji Pharmaceutical University for his critical review of the manuscript. We thank Masaaki Kozaki for his excellent technical assistance.

Author information

Authors and Affiliations

  1. Product Development Department, Pharmaceutical Division, Kirin Brewery Company Ltd, Shibuya-ku, Tokyo, Japan

    H Takama, H Tanaka & D Nakashima

  2. Department of International Medicine and Molecular Science, Nagoya City University Graduate School of Medical Science, Mizuho-ku, Nagoya, Aichi, Japan

    R Ueda

  3. Hematopoetic Stem Cell Transplantation Unit, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan

    Y Takaue

Authors
  1. H Takama
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D Nakashima
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R Ueda
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Y Takaue
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to H Takama.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Takama, H., Tanaka, H., Nakashima, D. et al. Population pharmacokinetics of intravenous busulfan in patients undergoing hematopoietic stem cell transplantation. Bone Marrow Transplant 37, 345–351 (2006). https://doi.org/10.1038/sj.bmt.1705252

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.bmt.1705252

Keywords

This article is cited by

Search

Advanced search

Quick links