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:

Drug Interactions

In children and adolescents, the pharmacodynamics of high-dose busulfan is dependent on the second alkylating agent used in the combined regimen (melphalan or thiotepa)

Bone Marrow Transplantation volume 32, pages 979–986 (2003)Cite this article

Summary:

A strong relationship has been demonstrated between high systemic exposure to busulfan and the occurrence of hepatic veno-occlusive disease (HVOD) after a busulfan–cyclophosphamide regimen (BU CY). We report a prospective study aimed at exploring the pharmacodynamics of high-dose busulfan combined with either melphalan (BU MEL) or thiotepa (BU TTP) followed by autologous stem cell transplantation in children and adolescents with a malignant solid tumor. Busulfan was given orally at a total dose of 600 mg m−2. In all, 45 patients with a median age of 6.3 years were included in the study: 25 received BU MEL and 20 received BU TTP. The incidence of HVOD was 44% (CI 95% [23–65%]) in the BU MEL group and 25% (CI95% [9–49%]) in the BU TTP group. In the BU TTP group, patients who developed HVOD had a significantly higher AUC 0-6 h after the 13th dose (6201±607 h ng ml−1) than those who did not (5024±978 h ng ml−1) (P<0.05). In the BU MEL group, there was no difference in terms of systemic exposure to busulfan between patients who developed HVOD and those who did not. In conclusion, the guidelines established for monitoring BU CY cannot be extrapolated when busulfan is combined with another drug.

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

Similar content being viewed by others

References

  1. Dunn CD . The chemical and biological properties of busulphan (“Myleran”). Exp Hematol 1974; 2: 101–117.

    CAS  PubMed  Google Scholar 

  2. Santos GW, Tutschka PJ, Brookmeyer R 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 

  3. Lenarsky C, Kohn DB, Weinberg KI, Parkman R . Bone marrow transplantation for genetic diseases. Hematol Oncol Clin North Am 1990; 4: 589–602.

    Article  CAS  PubMed  Google Scholar 

  4. Lenarsky C, Parkman R . Bone marrow transplantation for the treatment of immune deficiency states. Bone Marrow Transplant 1990; 6: 361–369.

    CAS  PubMed  Google Scholar 

  5. Santos GW . The development of busulfan/cyclophosphamide preparative regimens. Semin Oncol 1993; 20: 12–16.

    CAS  PubMed  Google Scholar 

  6. Hartmann O, Valteau-Couanet D, Vassal G et al. Prognostic factors in metastatic neuroblastoma in patients over 1 year of age treated with high-dose chemotherapy and stem cell transplantation: a multivariate analysis in 218 patients treated in a single institution. Bone Marrow Transplant 1999; 23: 789–795.

    Article  CAS  PubMed  Google Scholar 

  7. Valteau-Couanet D, Benhamou E, Vassal G et al. Consolidation with a busulfan-containing regimen followed by stem cell transplantation in infants with poor prognosis stage 4 neuroblastoma. Bone Marrow Transplant 2000; 25: 937–942.

    Article  CAS  PubMed  Google Scholar 

  8. Kalifa C, Hartmann O, Demeocq F et al. High-dose busulfan and thiotepa with autologous bone marrow transplantation in childhood malignant brain tumors: a phase II study. Bone Marrow Transplant 1992; 9: 227–233.

    CAS  PubMed  Google Scholar 

  9. Dupuis-Girod S, Hartmann O, Benhamou E et al. Will high dose chemotherapy followed by autologous bone marrow transplantation supplant cranio-spinal irradiation in young children treated for medulloblastoma? J Neurooncol 1996; 27: 87–98.

    Article  CAS  PubMed  Google Scholar 

  10. DeLeve LD, Shulman HM, McDonald GB . Toxic injury to hepatic sinusoids: sinusoidal obstruction syndrome (veno-occlusive disease). Semin Liver Dis 2002; 22: 27–42.

    Article  PubMed  Google Scholar 

  11. Bearman SI . Avoiding hepatic veno-occlusive disease: what do we know and where are we going? Bone Marrow Transplant 2001; 27: 1113–1120.

    Article  CAS  PubMed  Google Scholar 

  12. Meresse V, Hartmann O, Vassal G et al. Risk factors for hepatic veno-occlusive disease after high-dose busulfan-containing regimens followed by autologous bone marrow transplantation: a study in 136 children. Bone Marrow Transplant 1992; 10: 135–141.

    CAS  PubMed  Google Scholar 

  13. Grochow LB, Jones RJ, Brundrett RB 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 

  14. Hassan M, Ehrsson H, Ljungman P . Aspects concerning busulfan pharmacokinetics and bioavailability. Leuk Lymphoma 1996; 22: 395–407.

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  16. Slattery JT, Sanders JE, Buckner CD et al. Graft-rejection and toxicity following bone marrow transplantation in relation to busulfan pharmacokinetics [published erratum appears in Bone Marrow Transplant 1996 Oct; 18(4): 829]. Bone Marrow Transplant 1995; 16: 31–42.

    CAS  PubMed  Google Scholar 

  17. Bolinger AM, Zangwill AB, Slattery JT et al. An evaluation of engraftment, toxicity and busulfan concentration in children receiving bone marrow transplantation for leukemia or genetic disease. Bone Marrow Transplant 2000; 25: 925–930.

    Article  CAS  PubMed  Google Scholar 

  18. Sandstrom M, Karlsson MO, Ljungman P 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  CAS  PubMed  Google Scholar 

  19. Bolinger AM, Zangwill AB, Slattery JT et al. Target dose adjustment of busulfan in pediatric patients undergoing bone marrow transplantation. Bone Marrow Transplant 2001; 28: 1013–1018.

    Article  CAS  PubMed  Google Scholar 

  20. Slattery JT, Risler LJ . Therapeutic monitoring of busulfan in hematopoietic stem cell transplantation. Ther Drug Monit 1998; 20: 543–549.

    Article  CAS  PubMed  Google Scholar 

  21. Bleyzac N, Souillet G, Magron P et al. Improved clinical outcome of paediatric bone marrow recipients using a test dose and Bayesian pharmacokinetic individualization of busulfan dosage regimens. Bone Marrow Transplant 2001; 28: 743–751.

    Article  CAS  PubMed  Google Scholar 

  22. Vassal G, Koscielny S, Challine D et al. Busulfan disposition and hepatic veno-occlusive disease in children undergoing bone marrow transplantation. Cancer Chemother Pharmacol 1996; 37: 247–253.

    Article  CAS  PubMed  Google Scholar 

  23. McDonald GB, Hinds MS, Fisher LD et al. Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients. Ann Intern Med 1993; 118: 255–267.

    Article  CAS  PubMed  Google Scholar 

  24. 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 

  25. Vassal G, Deroussent A, Challine D et al. Is 600 mg/m2 the appropriate dosage of busulfan in children undergoing bone marrow transplantation? Blood 1992; 79: 2475–2479.

    CAS  PubMed  Google Scholar 

  26. Shumaker RC . PKCALC: a BASIC interactive computer program for statistical and pharmacokinetic analysis of data. Drug Metab Rev 1986; 17: 331–348.

    Article  CAS  PubMed  Google Scholar 

  27. Hassan M, Oberg G, Bekassy AN 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 

  28. Grochow LB, Krivit W, Whitley CB, Blazar B . Busulfan disposition in children. Blood 1990; 75: 1723–1727.

    CAS  PubMed  Google Scholar 

  29. Vassal G, Gouyette A, Hartmann O, Pico JL, Lemerle J . Pharmacokinetics of high-dose busulfan in children. Cancer Chemother Pharmacol 1989; 24: 386–390.

    Article  CAS  PubMed  Google Scholar 

  30. Dix SP, Wingard JR, Mullins RE 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 

  31. Schuler U, Schroer S, Kuhnle A et al. Busulfan pharmacokinetics in bone marrow transplant patients: is drug monitoring warranted? Bone Marrow Transplant 1994; 14: 759–765.

    CAS  PubMed  Google Scholar 

  32. Slattery JT, Kalhorn TF, McDonald GB et al. Conditioning regimen-dependent disposition of cyclophosphamide and hydroxycyclophosphamide in human marrow transplantation patients. J Clin Oncol 1996; 14: 1484–1494.

    Article  CAS  PubMed  Google Scholar 

  33. McCune JS, Gibbs JP, Slattery JT . Plasma concentration monitoring of busulfan: does it improve clinical outcome? Clin Pharmacokinet 2000; 39: 155–165.

    Article  CAS  PubMed  Google Scholar 

  34. McCune JS, Gooley T, Gibbs JP et al. Busulfan concentration and graft rejection in pediatric patients undergoing hematopoietic stem cell transplantation. Bone Marrow Transplant 2002; 30: 167–173.

    Article  CAS  PubMed  Google Scholar 

  35. Vassal G, Tranchand B, Valteau-Couanet D et al. Pharmacodynamics of tandem high-dose melphalan with peripheral blood stem cell transplantation in children with neuroblastoma and medulloblastoma. Bone Marrow Transplant 2001; 27: 471–477.

    Article  CAS  PubMed  Google Scholar 

  36. Vesole DH, Crowley JJ, Catchatourian R et al. High-dose melphalan with autotransplantation for refractory multiple myeloma: results of a Southwest Oncology Group phase II trial. J Clin Oncol 1999; 17: 2173–2179.

    Article  CAS  PubMed  Google Scholar 

  37. Czerwinski M, Gibbs JP, Slattery JT . Busulfan conjugation by glutathione S-transferases alpha, mu, and pi. Drug Metab Dispos 1996; 24: 1015–1019.

    CAS  PubMed  Google Scholar 

  38. Gibbs JP, Czerwinski M, Slattery JT . Busulfan–glutathione conjugation catalyzed by human liver cytosolic glutathione S-transferases. Cancer Res 1996; 56: 3678–3681.

    CAS  PubMed  Google Scholar 

  39. Paumi CM, Ledford BG, Smitherman PK et al. Role of multidrug resistance protein 1 (MRP1) and glutathione S-transferase A1-1 in alkylating agent resistance. Kinetics of glutathione conjugate formation and efflux govern differential cellular sensitivity to chlorambucil versus melphalan toxicity. J Biol Chem 2001; 276: 7952–7956.

    Article  CAS  PubMed  Google Scholar 

  40. Vahrmeijer AL, van Dierendonck JH, Schutrups J et al. Potentiation of the cytostatic effect of melphalan on colorectal cancer hepatic metastases by infusion of buthionine sulfoximine (BSO) in the rat: enhanced tumor glutathione depletion by infusion of BSO in the hepatic artery. Cancer Chemother Pharmacol 1999; 44: 111–116.

    Article  CAS  PubMed  Google Scholar 

  41. Anderson CP, Tsai J, Chan W et al. Buthionine sulphoximine alone and in combination with melphalan (L-PAM) is highly cytotoxic for human neuroblastoma cell lines. Eur J Cancer 1997; 33: 2016–2019.

    Article  CAS  PubMed  Google Scholar 

  42. Shulman HM, Luk K, Deeg HJ et al. Induction of hepatic veno-occlusive disease in dogs. Am J Pathol 1987; 126: 114–125.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. DeLeve LD, Wang X . Role of oxidative stress and glutathione in busulfan toxicity in cultured murine hepatocytes. Pharmacology 2000; 60: 143–154.

    Article  CAS  PubMed  Google Scholar 

  44. Hassan M, Ljungman P, Ringden O et al. The effect of busulphan on the pharmacokinetics of cyclophosphamide and its 4-hydroxy metabolite: time interval influence on therapeutic efficacy and therapy-related toxicity. Bone Marrow Transplant 2000; 25: 915–924.

    Article  CAS  PubMed  Google Scholar 

  45. Coles BF, Morel F, Rauch C et al. Effect of polymorphism in the human glutathione S-transferase A1 promoter on hepatic GSTA1 and GSTA2 expression. Pharmacogenetics 2001; 11: 663–669.

    Article  CAS  PubMed  Google Scholar 

  46. Nakajima T, Elovaara E, Anttila S et al. Expression and polymorphism of glutathione S-transferase in human lungs: risk factors in smoking-related lung cancer. Carcinogenesis 1995; 16: 707–711.

    Article  CAS  PubMed  Google Scholar 

  47. Balasubramanian P, Chandy M, Krishnamoorthy R, Srivastava A . Evaluation of existing limited sampling models for busulfan kinetics in children with beta thalassaemia major undergoing bone marrow transplantation. Bone Marrow Transplant 2001; 28: 821–825.

    Article  CAS  PubMed  Google Scholar 

  48. Bhagwatwar HP, Phadungpojna S, Chow DS, Andersson BS . Formulation and stability of busulfan for intravenous administration in high-dose chemotherapy. Cancer Chemother Pharmacol 1996; 37: 401–408.

    Article  CAS  PubMed  Google Scholar 

  49. Andersson BS, Madden T, Tran HT 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 

Download references

Acknowledgements

This study was supported by a grant from the ‘comité de recherche clinique’, Institut Gustave Roussy. We thank all the nursing staff of the bone marrow transplantation unit ‘La Mer’, Department of Paediatrics Oncology, Institut Gustave Roussy. We are grateful to Lorna Saint Ange for editing the manuscript.

Author information

Authors and Affiliations

  1. UPRES EA3535, Pharmacology and New Treatments of Cancers, Institut Gustave Roussy, rue Camille Desmoulins, Villejuif, France

    J Bouligand, I Boland & G Vassal

  2. Department of Paediatrics, Institut Gustave Roussy, rue Camille Desmoulins, Villejuif, France

    D Valteau-Couanet, C Kalifa, O Hartmann & G Vassal

  3. Mass Spectrometry Platform, Institut Fédératif de Recherche 54, Institut Gustave Roussy, rue Camille Desmoulins, Villejuif, France

    A Deroussent & G Vassal

Authors
  1. J Bouligand
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. I Boland
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D Valteau-Couanet
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Deroussent
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C Kalifa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. O Hartmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. G Vassal
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to G Vassal.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bouligand, J., Boland, I., Valteau-Couanet, D. et al. In children and adolescents, the pharmacodynamics of high-dose busulfan is dependent on the second alkylating agent used in the combined regimen (melphalan or thiotepa). Bone Marrow Transplant 32, 979–986 (2003). https://doi.org/10.1038/sj.bmt.1704275

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.bmt.1704275

Keywords

This article is cited by

Search

Advanced search

Quick links