Skip to main content

Advertisement

SpringerLink
Log in

Trough level monitoring of intravenous busulfan to estimate the area under the plasma drug concentration–time curve in pediatric hematopoietic stem cell transplant recipients

  • Original Article
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

Optimizing systemic busulfan exposure, the area under the concentration–time curve (AUC), improves the outcomes for hematopoietic stem cell transplantation (HSCT). The AUC is conventionally calculated using six plasma concentrations (AUC0–∞) drawn after the first of 16 intravenous busulfan doses given as a 2-h infusion every 6 h. The aim of the present study was to develop limited sampling strategies using three or fewer busulfan concentrations to reliably calculate AUC0–∞ in patients undergoing HSCT. We investigated the pharmacokinetics of busulfan 46 times in 29 pediatric patients receiving intravenous busulfan. Limited sampling strategies using one, two, or three plasma busulfan concentrations were developed by multiple linear regression that showed excellent agreement with AUC0–∞. In single-point sampling strategies, the AUC0–∞ predicted based on C6 (trough level: busulfan plasma concentration 6 h after the start of the infusion) was significantly correlated with, and not statistically different from, actual values as follows: AUC0–∞ = 2556.5 C6 + 320.9 (r 2 = 0.929, P < 0.0001, mean bias 0.282 %, precision 7.91 %). In contrast, the predicted AUCs derived from the other sampling single points did not meet the criteria. The trough level well correlated with actual AUC0–∞, suggesting that this time-point is acceptable for busulfan monitoring.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Hoy SM, Lyseng-Williamson KA. Intravenous busulfan in the conditioning treatment of pediatric patients prior to hematopoietic stem cell transplantation. Paediatr Drugs. 2007;9:271–8.

    Article  PubMed  Google Scholar 

  2. Bredeson C, LeRademacher J, Kato K, Dipersio JF, Agura E, Devine SM, et al. Prospective cohort study comparing intravenous busulfan to total body irradiation in hematopoietic cell transplantation. Blood. 2013;122(24):3871–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. 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 

  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;17:225–30.

    CAS  PubMed  Google Scholar 

  5. Michel G, Valteau-Couanet D, Gentet JC, Esperou H, Socié G, Méchinaud F, et al. Weight-based strategy of dose administration in children using intravenous busulfan: clinical and pharmacokinetic results. Pediatr Blood Cancer. 2012;58(1):90–7.

    Article  PubMed  Google Scholar 

  6. Nagasawa M, Mitsuiki N, Ono T, Takagi M, Oda H, Yasuhara M, et al. Pharmacokinetic monitoring is still required for intravenous busulfan in SCT for small children. Int J Hematol. 2010;91(4):728–30.

    Article  PubMed  Google Scholar 

  7. Sato M, Kako S, Matsumoto K, Oshima K, Akahoshi Y, Nakano H, et al. Pharmacokinetics study of once-daily intravenous busulfan in conditioning regimens for hematopoietic stem cell transplantation. Int J Hematol. 2015;101(5):497–504.

    Article  CAS  PubMed  Google Scholar 

  8. Russell JA, Kangarloo SB. Therapeutic drug monitoring of busulfan in transplantation. Curr Pharm Des. 2008;14(20):1936–49.

    Article  CAS  PubMed  Google Scholar 

  9. 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(10):979–87.

    Article  CAS  PubMed  Google Scholar 

  10. Henner WD, Furlong EA, Flaherty MD, Shea TC, Peters WP. Measurement of busulfan in plasma by high-performance liquid chromatography. J Chromatogr. 1987;416:426–32.

    Article  CAS  PubMed  Google Scholar 

  11. Yamaoka K, Nakagawa T, Uno T. Statistical moments in pharmacokinetics. J Pharmacokinet Biopharm. 1978;6(6):547–58.

    Article  CAS  PubMed  Google Scholar 

  12. Nishikawa T, Okamoto Y, Tanabe T, Shinkoda Y, Kodama Y, Higashi M, et al. Unexpectedly high AUC levels in a child who received intravenous busulfan before stem cell transplantation. Bone Marrow Transplant. 2010;45(3):602–4.

    Article  CAS  PubMed  Google Scholar 

  13. Okamoto Y, Nagatoshi Y, Kosaka Y, Kikuchi A, Kato S, Kigasawa H, et al. Prospective pharmacokinetic study of intravenous busulfan in hematopoietic stem cell transplantation in 25 children. Pediatr Transplant. 2014;18(3):294–301.

    Article  CAS  PubMed  Google Scholar 

  14. Zao JH, Schechter T, Liu WJ, Gerges S, Gassas A, Egeler RM, et al. Performance of busulfan dosing guidelines for pediatric hematopoietic stem cell transplant conditioning. Biol Blood Marrow Transplant. 2015;21(8):1471–8.

    Article  CAS  PubMed  Google Scholar 

  15. Takamatsu Y, Sasaki N, Eto T, Nagafuji K, Abe Y, Choi I, et al. Individual dose adjustment of oral busulfan using a test dose in hematopoietic stem cell transplantation. Int J Hematol. 2007;86(3):261–8.

    Article  CAS  PubMed  Google Scholar 

  16. Beri R, Chunduri S, Sweiss K, Peace DJ, Mactal-Haaf C, Dobogai LC, et al. Reliability of a pretransplant i.v. BU test dose performed 2 weeks before myeloablative FluBu conditioning regimen. Bone Marrow Transplant. 2010;45(2):249–53.

    Article  CAS  PubMed  Google Scholar 

  17. Spasojevic I, da Costa LR, Horwitz ME, Long GD, Sullivan KM, Chute JP, et al. Mini test dose of intravenous busulfan (busulfex(®)) in allogeneic non-myeloablative stem cell transplantation, followed by liquid chromatography tandem-mass spectrometry. Cancer Invest. 2012;30(9):679–82.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Nguyen L, Leger F, Lennon S, Puozzo C. Intravenous busulfan in adults prior to haematopoietic stem cell transplantation: a population pharmacokinetic study. Cancer Chemother Pharmacol. 2006;57(2):191–8.

    Article  CAS  PubMed  Google Scholar 

  19. Dupuis LL, Sibbald C, Schechter T, Ansari M, Gassas A, Théorêt Y, et al. IV busulfan dose individualization in children undergoing hematopoietic stem cell transplant: limited sampling strategies. Biol Blood Marrow Transplant. 2008;14(5):576–82.

    Article  CAS  PubMed  Google Scholar 

  20. Xie HG, Kim RB, Wood AJ, Stein CM. Molecular basis of ethnic differences in drug disposition and response. Annu Rev Pharmacol Toxicol. 2001;41:815–50.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported in part by funds for Grant-in-Aid for Young Scientists (B) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (Grant Number #26870460 to TN).

Author information

Author notes

    Authors and Affiliations

    1. Department of Clinical Pharmacy and Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan

      Erika Watanabe, Kazuaki Matsumoto & Yasuo Takeda

    2. Department of Pediatrics, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, 890-8520, Japan

      Takuro Nishikawa, Takanari Abematsu, Shunsuke Nakagawa, Koichiro Kurauchi, Yuichi Kodama, Takayuki Tanabe, Yasuhiro Okamoto & Yoshifumi Kawano

    3. Department of Clinical Pharmacotherapy, Hiroshima University, Hiroshima, Japan

      Kazuro Ikawa

    4. Department of Hematology, Nippon Medical School, Tokyo, Japan

      Hiroki Yamaguchi

    5. Department of Pediatrics, Kagoshima City Hospital, Kagoshima, Japan

      Yuichi Shinkoda

    Authors
    1. Erika Watanabe
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Takuro Nishikawa
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Kazuro Ikawa
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Hiroki Yamaguchi
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Takanari Abematsu
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Shunsuke Nakagawa
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Koichiro Kurauchi
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Yuichi Kodama
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Takayuki Tanabe
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Yuichi Shinkoda
      View author publications

      You can also search for this author in PubMed Google Scholar

    11. Kazuaki Matsumoto
      View author publications

      You can also search for this author in PubMed Google Scholar

    12. Yasuhiro Okamoto
      View author publications

      You can also search for this author in PubMed Google Scholar

    13. Yasuo Takeda
      View author publications

      You can also search for this author in PubMed Google Scholar

    14. Yoshifumi Kawano
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Takuro Nishikawa.

    Ethics declarations

    Conflict of interest

    None.

    Additional information

    E. Watanabe and T. Nishikawa have contributed equally to this work.

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Watanabe, E., Nishikawa, T., Ikawa, K. et al. Trough level monitoring of intravenous busulfan to estimate the area under the plasma drug concentration–time curve in pediatric hematopoietic stem cell transplant recipients. Int J Hematol 102, 611–616 (2015). https://doi.org/10.1007/s12185-015-1853-6

    Download citation

    • Received:

    • Revised:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s12185-015-1853-6

    Keywords

    Search

    Navigation