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

Pharmacokinetics of liposomal busulphan in man

Bone Marrow Transplantation volume 27, pages 479–485 (2001)Cite this article

Abstract

High doses of busulphan are used in conditioning regimens before stem cell transplantation. Great inter-patient variations in pharmacokinetics and a correlation between toxicity and high systemic exposure of busulphan have been shown in several studies. Some authors have suggested therapeutic drug monitoring and intravenous busulphan aiming to reduce the conditioning-related toxicity. Liposomal busulphan (LBu) might be an alternative to intravenous administration of high-dose busulphan in conditioning. In the present study, we investigated the pharmacokinetics of LBu in man. Seventeen consecutive patients were enrolled in the study. LBu as a single low dose (2 to 8 mg) was given to 12 patients (six adults and six children). Five patients received two high doses of LBu which replaced the first and the last doses of the conditioning regimen. The high dose of LBu was raised from 0.4 to 0.9 mg/kg. A significant linear correlation (r2 = 0.928) was found between the dose of LBu and the area under the plasma concentration-time curve (AUC) (P < 0.001). AUC corrected for 1 mg/kg was 5491 ± 912 ng·h/ml and 5955 ± 627 ng·h/ml (low dose of LBu in children and adults, respectively) and 6167 ± 1385 ng·h/ml and 6933 ± 656 ng·h/ml (ie the first and the last high doses of LBu, respectively). No significant correlation was found between clearance and age or apparent volume of distribution and age (r2 = 0.146 and r2 = 0.046, respectively). No toxicity related to the liposomal formulation of busulphan was observed. We conclude that LBu is suitable for conditioning before stem cell transplantation. Bone Marrow Transplantation (2001) 27, 479–485.

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. Blaise D, Maraninchi D, Archimbaud E et al. Allogeneic bone marrow transplantation for acute myeloid leukemia in first remission: a randomized trial of a busulfan-cytoxan versus cytoxan-total body irradiation as preparative regimen: a report from the Group d'Etudes de la Greffe de Moelle Osseuse (see comments) Blood 1992 79: 2578–2582

    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 New Engl J Med 1983 309: 1347–1353

    Article  CAS  PubMed  Google Scholar 

  3. Blume KG, Kopecky KJ, Henslee-Downey JP et al. A prospective randomized comparison of total body irradiation-etoposide versus busulfan-cyclophosphamide as preparatory regimens for bone marrow transplantation in patients with leukemia who were not in first remission: a Southwest Oncology Group study Blood 1993 81: 2187–2193

    CAS  PubMed  Google Scholar 

  4. Ringden O, Ruutu T, Remberger M et al. A randomized trial comparing busulfan with total body irradiation as conditioning in allogeneic marrow transplant recipients with leukemia: a report from the Nordic Bone Marrow Transplantation Group Blood 1994 83: 2723–2730

    CAS  PubMed  Google Scholar 

  5. Ringden O, Labopin M, Tura S et al. A comparison of busulphan versus total body irradiation combined with cyclophosphamide as conditioning for autograft or allograft bone marrow transplantation in patients with acute leukaemia. Acute Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT) Br J Haematol 1996 93: 637–645

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  7. 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 

  8. Vassal G, Fischer A, Challine D et al. Busulfan disposition below the age of three: alteration in children with lysosomal storage disease Blood 1993 82: 1030–1034

    CAS  PubMed  Google Scholar 

  9. Hassan M, Ljungman P, Bolme P et al. Busulfan bioavailability Blood 1994 84: 2144–2150

    CAS  PubMed  Google Scholar 

  10. 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 

  11. Vassal G, Deroussent A, Hartmann O et al. Dose-dependent neurotoxicity of high-dose busulfan in children: a clinical and pharmacological study Cancer Res 1990 50: 6203–6207

    CAS  PubMed  Google Scholar 

  12. Hassan M, Fasth A, Gerritsen B 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 

  13. Chattergoon DS, Saunders EF, Klein J et al. An improved limited sampling method for individualised busulphan dosing in bone marrow transplantation in children Bone Marrow Transplant 1997 20: 347–354

    Article  CAS  PubMed  Google Scholar 

  14. Ehninger G, Schuler U, Renner U et al. Use of a water-soluble busulfan formulation – pharmacokinetic studies in a canine model Blood 1995 85: 3247–3249

    CAS  PubMed  Google Scholar 

  15. 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 

  16. Schuler US, Ehrsam M, Schneider A et al. Pharmacokinetics of intravenous busulfan and evaluation of the bioavailability of the oral formulation in conditioning for haematopoietic stem cell transplantation Bone Marrow Transplant 1998 22: 241–244

    Article  CAS  PubMed  Google Scholar 

  17. Kennedy GL Jr, Sherman H . Acute and subchronic toxicity of dimethylformamide and dimethylacetamide following various routes of administration Drug Chem Toxicol 1986 9: 147–170

    Article  PubMed  Google Scholar 

  18. Kinney LA, Burgess BA, Stula EF, Kennedy GL Jr . Inhalation studies in rats exposed to dimethylacetamide (DMAc) from 3 to 12 hours per day Drug Chem Toxicol 1993 16: 175–194

    Article  CAS  PubMed  Google Scholar 

  19. Yellowlees P, Greenfield C, McIntyre N . Dimethylsulphoxide-induced toxicity Lancet 1980 2: 1004–1006

    Article  CAS  PubMed  Google Scholar 

  20. Olavarria E, Hassan M, Eades A 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 

  21. Hassan M, Hassan Z, Nilsson C et al. Pharmacokinetics and distribution of liposomal busulfan in the rat: a new formulation for intravenous administration Cancer Chemother Pharmacol 1998 42: 471–478

    Article  CAS  PubMed  Google Scholar 

  22. Hassan Z, Nilsson C, Hassan M . Liposomal busulphan: bioavailability and effect on bone marrow in mice Bone Marrow Transplant 1998 22: 913–918

    Article  CAS  PubMed  Google Scholar 

  23. Ostro MJ, Cullis PR . Use of liposomes as injectable-drug delivery systems Am J Hosp Pharm 1989 46: 1576–1587

    CAS  PubMed  Google Scholar 

  24. Lopez-Berestein G, Fainstein V, Hopfer R et al. Liposomal amphotericin B for the treatment of systemic fungal infections in patients with cancer: a preliminary study J Infect Dis 1985 151: 704–710

    Article  CAS  PubMed  Google Scholar 

  25. Tollemar J, Ringdén O, Tydén G . Liposomal amphotericin B (AmBisome) treatment in solid organ and bone marrow transplant recipients. Efficacy and safety evaluation Clin Transplant 1990 4: 167–175

    Google Scholar 

  26. Hassan M, Ehrsson H . Gas chromatographic determination of busulfan in plasma with electron-capture detection J Chromatogr 1983 277: 374–380

    Article  CAS  PubMed  Google Scholar 

  27. Vassal G, Challine D, Koscielny S et al. Chronopharmacology of high-dose busulfan in children Cancer Res 1993 53: 1534–1537

    CAS  PubMed  Google Scholar 

  28. Ljungman P, Hassan M, Bekassy AN et al. High busulfan concentrations are associated with increased transplant-related mortality in allogeneic bone marrow transplant patients Bone Marrow Transplant 1997 20: 909–913

    Article  CAS  PubMed  Google Scholar 

  29. Gibbs JP, Murray G, Risler L et al. Age-dependent tetrahydrothiophenium ion formation in young children and adults receiving high-dose busulfan Cancer Res 1997 57: 5509–5516

    CAS  PubMed  Google Scholar 

  30. Vassal G, Gouyette A, Hartmann O et al. Pharmacokinetics of high-dose busulfan in children Cancer Chemother Pharmacol 1989 24: 386–390

    Article  CAS  PubMed  Google Scholar 

  31. Shaw PJ, Scharping CE, Brian RJ, Earl JW . Busulfan pharmacokinetics using a single daily high-dose regimen in children with acute leukemia Blood 1994 84: 2357–2362

    CAS  PubMed  Google Scholar 

  32. Regazzi MB, Locatelli F, Buggia I et al. Disposition of high-dose busulfan in pediatric patients undergoing bone marrow transplantation Clin Pharmacol Ther 1993 54: 45–52

    Article  CAS  PubMed  Google Scholar 

  33. Janoff A (ed) . Liposomes: Rational Design Marcel Dekker: New York 1999 p 324

    Google Scholar 

Download references

Acknowledgements

This study was supported by grants from the Swedish Children's Cancer Society (grant 1997/035, 1999/033), King's Gustaf V Jubilee Fund (grant 00:510) and the Mary Bèves Stiftelse. The authors thank the nursing staff on wards B87, B78 and M72, Huddinge University Hospital for all their help during the study.

Author information

Authors and Affiliations

  1. Department of Medicine, Division of Hematology, Karolinska Institutet at Huddinge University Hospital, Sweden

    Z Hassan, P Ljungman, C Nilsson, J Aschan, HRosengren Whitley & M Hassan

  2. Center for Allogeneic Stem Cell Transplantation, Karolinska Institutet at Huddinge University Hospital, Sweden

    O Ringdén & J Aschan

  3. Department of Pediatrics, Karolinska Institutet at Huddinge University Hospital, Sweden

    J Winiarski

Authors
  1. Z Hassan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P Ljungman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. O Ringdén
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J Winiarski
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C Nilsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J Aschan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. HRosengren Whitley
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M Hassan
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hassan, Z., Ljungman, P., Ringdén, O. et al. Pharmacokinetics of liposomal busulphan in man. Bone Marrow Transplant 27, 479–485 (2001). https://doi.org/10.1038/sj.bmt.1702823

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.bmt.1702823

Keywords

This article is cited by

Search

Advanced search

Quick links