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:

Pharmacokinetics

Oral busulfan pharmacokinetics and engraftment in children with Hurler syndrome and other inherited metabolic storage diseases undergoing hematopoietic cell transplantation

Bone Marrow Transplantation volume 27, pages 855–861 (2001)Cite this article

Abstract

Allogeneic hematopoietic cell transplantation (HCT) is the only treatment for selected inherited metabolic storage diseases (IMSD); a significant shortcoming is failure to achieve donor-derived engraftment. This study was undertaken to determine whether busulfan pharmacokinetics (BU PK) are altered in children with IMSD and whether BU concentrations are important in achieving engraftment. BU samples were obtained from 39 IMSD children, including 20 children with Hurler syndrome, undergoing HCT. Patients received oral BU (40 mg/m2/dose × 8 doses), cyclophosphamide (60 mg/kg/day × 2 doses) and TBI (750 cGy in one fraction) as a preparative regimen. Median (range) oral clearance corrected for bioavailability (Cl/F in ml/min/kg), area under the curve (AUC in ng min/ml) and BU plasma concentration (Cp in ng/ml) with the fourth dose were 5.2 (2.1–11.4), 318 294 (112 893–640 995) and 950 (314–1780), respectively. Children <3 years of age had lower AUC and Cp but higher Cl/F (P ⩽ 0.03). BU Cp (P = 0.06) or marrow cell dose (P = 0.32) was not different in Hurler syndrome compared to other IMSD. A median BU Cp of 959 and 831 ng/ml was achieved in children with full and failed early engraftment, respectively. There was no difference in early and late engraftment between children with Hurler and other IMSD. In conclusion, we found no significant association between engraftment, marrow cell dose and BU exposure when combined with CY and TBI in children with IMSD. Bone Marrow Transplantation (2001) 27, 855–861.

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

Similar content being viewed by others

References

  1. Hobbs JR, Hugh-Jones K, Barrett AJ et al. Reversal of clinical features of Hurler's disease and biochemical improvement after treatment by bone-marrow transplantation Lancet 1981 2: 709–712

    Article  CAS  PubMed  Google Scholar 

  2. Krivit W, Pierpont ME, Ayaz K et al. Bone-marrow transplantation in the Maroteaux–Lamy syndrome (mucopoly-saccharidosis type VI). Biochemical and clinical status 24 months after transplantation New Engl J Med 1984 311: 1606–1611

    Article  CAS  PubMed  Google Scholar 

  3. Wall DA, Grange DK, Goulding P et al. Bone marrow transplantation for the treatment of alpha-mannosidosis J Pediatr 1998 133: 282–285

    Article  CAS  PubMed  Google Scholar 

  4. Aubourg P, Blanche S, Jambaque I et al. Reversal of early neurologic and neuroradiologic manifestations of X-linked adrenoleukodystrophy by bone marrow transplantation New Engl J Med 1990 322: 1860–1866

    Article  CAS  PubMed  Google Scholar 

  5. Krivit W, Shapiro E, Kennedy W et al. Treatment of late infantile metachromatic leukodystrophy by bone marrow transplantation (see comments) New Engl J Med 1990 322: 28–32

    Article  CAS  PubMed  Google Scholar 

  6. Krivit W, Shapiro EG, Peters C et al. Hematopoietic stem-cell transplantation in globoid-cell leukodystrophy New Engl J Med 1998 338: 1119–1126

    Article  CAS  PubMed  Google Scholar 

  7. Peters C, Balthazor M, Shapiro EG et al. Outcome of unrelated donor bone marrow transplantation in 40 children with Hurler syndrome Blood 1996 87: 4894–4902

    CAS  PubMed  Google Scholar 

  8. Peters C, Shapiro EG, Anderson J et al. Hurler syndrome: II. Outcome of HLA-genotypically identical sibling and HLA-haploidentical related donor bone marrow transplantation in fifty-four children. The Storage Disease Collaborative Study Group Blood 1998 91: 2601–2608

    CAS  PubMed  Google Scholar 

  9. 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 

  10. Yeager AM, Wagner JE Jr, Graham ML et al. Optimization of busulfan dosage in children undergoing bone marrow transplantation: a pharmacokinetic study of dose escalation Blood 1992 80: 2425–2428

    CAS  PubMed  Google Scholar 

  11. 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 

  12. 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 

  13. Gibbs JP, Liacouras CA, Baldassano RN, Slattery JT . Up-regulation of glutathione S-transferase activity in enterocytes of young children Drug Metab Dispos 1999 27: 1466–1469

    CAS  PubMed  Google Scholar 

  14. 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 

  15. 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 

  16. Byrne JL, Stainer C, Cull G et al. The effect of the serotherapy regimen used and the marrow cell dose received on rejection, graft-versus-host disease and outcome following unrelated donor bone marrow transplantation for leukaemia Bone Marrow Transplant 2000 25: 411–417

    Article  CAS  PubMed  Google Scholar 

  17. Ringden O, Remberger M, Runde V et al. Peripheral blood stem cell transplantation from unrelated donors: a comparison with marrow transplantation Blood 1999 94: 455–464

    CAS  PubMed  Google Scholar 

  18. Gorin NC, Labopin M, Laporte JP et al. Importance of marrow dose on posttransplant outcome in acute leukemia: models derived from patients autografted with mafosfamide-purged marrow at a single institution Exp Hematol 1999 27: 1822–1830

    Article  CAS  PubMed  Google Scholar 

  19. Reisner Y, Martelli MF . Stem cell escalation enables HLA-disparate haematopoietic transplants in leukaemia patients Immunol Today 1999 20: 343–347

    Article  CAS  PubMed  Google Scholar 

  20. Cornetta K, Gharpure V, Mills B et al. Rapid engraftment after allogeneic transplantation using CD34-enriched marrow cells Bone Marrow Transplant 1998 21: 65–71

    Article  CAS  PubMed  Google Scholar 

  21. Clarke E, Potter MN, Hale G et al. Double T cell depletion of bone marrow using sequential positive and negative cell immunoaffinity or CD34+ cell selection followed by Campath-1M; effect on CD34+ cells and progenitor cell recoveries Bone Marrow Transplant 1998 22: 117–124

    Article  CAS  PubMed  Google Scholar 

  22. O'Donnell PV, Jones RJ, Vogelsang GB et al. CD34+ stem cell augmentation of elutriated allogeneic bone marrow grafts: results of a phase II clinical trial of engraftment and graft-versus-host disease prophylaxis in high-risk hematologic malignancies Bone Marrow Transplant 1998 22: 947–955

    Article  CAS  PubMed  Google Scholar 

  23. Wagner JE, Santos GW, Noga SJ et al. Bone marrow graft engineering by counterflow centrifugal elutriation: results of a phase I–II clinical trial Blood 1990 75: 1370–1377

    CAS  PubMed  Google Scholar 

  24. 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 

  25. Snedecor G, Cochran W . Statistical Methods, 8th edn Iowa State University Press: Ames, IA 1989

    Google Scholar 

  26. Kaplan EM, Meier P . Non parametric estimation from incomplete observations J Am Stat Assoc 1958 53: 457

    Article  Google Scholar 

  27. 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 

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

    CAS  PubMed  Google Scholar 

  29. 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 

  30. 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 

  31. Pawlowska AB, Blazar BR, Angelucci E et al. Relationship of plasma pharmacokinetics of high-dose oral busulfan to the outcome of allogeneic bone marrow transplantation in children with thalassemia Bone Marrow Transplant 1997 20: 915–920.

    Article  CAS  PubMed  Google Scholar 

  32. Gupta P, McCarthy JB, Verfaillie CM . Stromal fibroblast heparan sulfate is required for cytokine-mediated ex vivo maintenance of human long-term culture-initiating cells Blood 1996 87: 3229–3236

    CAS  PubMed  Google Scholar 

  33. Gupta P, Oegema TR Jr, Brazil JJ et al. Structurally specific heparan sulfates support primitive human hematopoiesis by formation of a multimolecular stem cell niche Blood 1998 92: 4641–4651

    CAS  PubMed  Google Scholar 

  34. Ringden O, Remberger M, Ruutu T et al. Increased risk of chronic graft-versus-host disease, obstructive bronchiolitis, and alopecia with busulfan versus total body irradiation: long-term results of a randomized trial in allogeneic marrow recipients with leukemia. Nordic Bone Marrow Transplantation Group (see comments) Blood 1999 93: 2196–2201.

    CAS  PubMed  Google Scholar 

  35. Styler MJ, Crilley P, Biggs J et al. Hepatic dysfunction following busulfan and cyclophosphamide myeloablation: a retrospective, multicenter analysis Bone Marrow Transplant 1996 18: 171–176

    CAS  PubMed  Google Scholar 

  36. Ozkaynak MF, Weinberg K, Kohn D et al. Hepatic veno-occlusive disease post-bone marrow transplantation in children conditioned with busulfan and cyclophosphamide: incidence, risk factors, and clinical outcome Bone Marrow Transplant 1991 7: 467–474

    CAS  PubMed  Google Scholar 

  37. Brodsky R, Topolsky D, Crilley P et al. Frequency of veno-occlusive disease of the liver in bone marrow transplantation with a modified busulfan/cyclophosphamide preparative regimen Am J Clin Oncol 1990 13: 221–225

    Article  CAS  PubMed  Google Scholar 

  38. Hartman AR, Williams SF, Dillon JJ . Survival, disease-free survival and adverse effects of conditioning for allogeneic bone marrow transplantation with busulfan/cyclophosphamide vs total body irradiation: a meta-analysis Bone Marrow Transplant 1998 22: 439–443

    Article  CAS  PubMed  Google Scholar 

  39. Bandini G, Belardinelli A, Rosti G et al. Toxicity of high-dose busulphan and cyclophosphamide as conditioning therapy for allogeneic bone marrow transplantation in adults with haematological malignancies Bone Marrow Transplant 1994 13: 577–581

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We wish to thank the nursing staff in the Pediatric Blood and Marrow Transplant Unit at Fairview-University Medical Center for the collection of blood samples and to recognize our collaborators at Duke University, All Children's Hospital in St Petersburg, FL, and Children's Hospital of Philadelphia for contributing patient samples for pharmacokinetic analysis. This work was supported in part by a grant from the Children's Cancer Research Fund (CP) and by National Institutes of Health Grant No. NS-29099 (WK).

Author information

Authors and Affiliations

  1. Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA

    P Jacobson

  2. Department of Pharmacy, Swedish Medical Center, Seattle, WA, USA

    JJ Park

  3. Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA

    TE DeFor, M Thrall, S Abel, W Krivit & C Peters

Authors
  1. P Jacobson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. JJ Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. TE DeFor
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Thrall
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S Abel
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. W Krivit
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. C Peters
    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

Jacobson, P., Park, J., DeFor, T. et al. Oral busulfan pharmacokinetics and engraftment in children with Hurler syndrome and other inherited metabolic storage diseases undergoing hematopoietic cell transplantation. Bone Marrow Transplant 27, 855–861 (2001). https://doi.org/10.1038/sj.bmt.1703010

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.bmt.1703010

Keywords

This article is cited by

Search

Advanced search

Quick links