Skip to main content

Advertisement

SpringerLink
Log in

Pharmacokinetic and pharmacodynamic analysis of cyclosporine A (CsA) to find the best single time point for the monitoring and adjusting of CsA dose using twice-daily 3-h intravenous infusions in allogeneic hematopoietic stem cell transplantation

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

Abstract

Pharmacological study is predictably effective in establishing an optimal monitoring strategy for the usage of cyclosporine A (CsA) to prevent graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplantation recipients. Pharmacokinetic profiling of 33 recipients administered CsA twice daily by 3-h intravenous infusion revealed that levels peaked 2–3 h after the start of infusion, and an exponential decline of CsA concentrations after the termination of infusion was observed. The correlation between the area under the curve (AUC0–12) and CsA concentration at various time points after infusion revealed that C 2 and C 3 correlated best with AUC0–12 (r 2 = 0.725), while the trough concentration correlated poorly. Ex vivo T cell stimulation followed by intracellular cytokine detection with flow cytometry revealed that the capacity of T cells to produce cytokines upon stimulation was inversely proportional to the CsA concentration, and reached a minimum at about 700 ng/mL with a marginal decrease above this concentration. Extrapolation using the regression equations of this study and the data from our retrospective study leads to the assumption that the dose adjustment of CsA based on maintaining the C 3 concentration above 800 ng/mL may effectively prevent acute GVHD. To confirm this assumption, a prospective clinical study is required.

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
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Ferrara JL, Cooke KR, Teshima T. The pathophysiology of acute graft-versus-host disease. Int J Hematol. 2003;78:181–7.

    Article  CAS  PubMed  Google Scholar 

  2. Ferrara JL, Levine JE, Reddy P, Holler E. Graft-versus-host disease. Lancet. 2009;373:1550–61.

    Article  CAS  PubMed  Google Scholar 

  3. Devergie A. Graft vs. host disease. In: Apperley J, Carreras E, Gluckman E, Gratwohl A, Masszi T, editors. Haemopoietic stem cell transplantation, the EBMT Handbook 2004 revised edn. Forum Service Editore; 2004. p.162–77.

  4. Chao NJ, Sullivan KM. Pharmacologic prevention of acute graft-versus-host disease. In: Appelbaum FR, Forman SJ, Negrin RS, Blume KG, editors. Thomas’ hematopoietic cell transplantation, 4th edn. Blackwell Publishing; 2009. p. 1257–74.

  5. Ruutu T, Niederwieser D, Gratwohl A, Apperley JF. A survey of the prophylaxis and treatment of acute GVHD in Europe: a report of the European Group for Blood and Marrow, Transplantation (EBMT). Chronic Leukaemia Working Party of the EBMT. Bone Marrow Transpl. 1997;19:759–64.

    Article  CAS  Google Scholar 

  6. Halloran PF, Helms LM, Kung L, Noujaim J. The temporal profile of calcineurin inhibition by cyclosporine in vivo. Transplantation. 1999;68:1356–61.

    Article  CAS  PubMed  Google Scholar 

  7. Sindhi R, LaVia MF, Paulling E, McMichael J, Burckart G, Shaw S, et al. Stimulated response of peripheral lymphocytes may distinguish cyclosporine effect in renal transplant recipients receiving a cyclosporine + rapamycin regimen. Transplantation. 2000;69:432–6.

    Article  CAS  PubMed  Google Scholar 

  8. Kahan BD. Therapeutic drug monitoring of cyclosporine: 20 years of progress. Transpl Proc. 2004;36(Suppl 2S):378S–91S.

    Article  Google Scholar 

  9. Nashan B, Cole E, Levy G, Thervet E. Clinical validation studies of Neoral C(2) monitoring: a review. Transplantation. 2002;73:S3–11.

    Article  PubMed  Google Scholar 

  10. Levy G, Thervet E, Lake J, Uchida K. Consensus on Neoral C(2) Expert Review in Transplantation (CONCERT) Group. Patient management by Neoral C(2) monitoring: an international consensus statement. Transplantation. 2002;73:S12–8.

    Article  PubMed  Google Scholar 

  11. Knight SR, Morris PJ. The clinical benefits of cyclosporine C2-level monitoring a systematic review. Transplantation. 2007;83:1525–35.

    Article  CAS  PubMed  Google Scholar 

  12. Duncan N, Craddock C. Optimizing the use of cyclosporin in allogeneic stem cell transplantation. Bone Marrow Transpl. 2006;38:169–74.

    Article  CAS  Google Scholar 

  13. Izumi N, Furukawa T, Sato N, Okazuka K, Tsukada N, Abe T, et al. Risk factors for acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation: retrospective analysis of 73 patients who received cyclosporin A. Bone Marrow Transpl. 2007;40:875–80.

    Article  CAS  Google Scholar 

  14. Sato N, Furukawa T, Kuroha T, Hashimoto S, Masuko M, Takahashi H, et al. High-dose cytosine arabinoside and etoposide with total body irradiation as a preparatory regimen for allogeneic hematopoietic stem-cell transplantation in patients with acute lymphoblastic leukemia. Bone Marrow Transpl. 2004;34:299–303.

    Article  CAS  Google Scholar 

  15. Picker LJ, Singh MK, Zdraveski Z, Treer JR, Waldrop SL, Bergstresser PR, et al. Direct demonstration of cytokine synthesis heterogeneity among human memory/effector T cells by flow cytometry. Blood. 1995;86:1408–19.

    CAS  PubMed  Google Scholar 

  16. Fukudo M, Yano I, Masuda S, Fukatsu S, Katsura T, Ogura Y, et al. Pharmacodynamic analysis of tacrolimus and cyclosporine in living-donor liver transplant patients. Clin Pharmacol Ther. 2005;78:168–81.

    Article  CAS  PubMed  Google Scholar 

  17. Batiuk TD, Pazderka F, Enns J, DeCastro L, Halloran PF. Cyclosporine inhibition of calcineurin activity in human leukocytes in vivo is rapidly reversible. J Clin Invest. 1995;96:1254–60.

    Article  CAS  PubMed  Google Scholar 

  18. Hendriks MP, Blijlevens NM, Schattenberg AV, Burger DM, Donnelly JP. Cyclosporine short infusion and C2 monitoring in haematopoietic stem cell transplant recipients. Bone Marrow Transpl. 2006;38:521–5.

    Article  CAS  Google Scholar 

  19. Nawa Y, Hara M, Tanimoto K, Nakase K, Kozuka T, Maeda Y. Single-dose daily infusion of cyclosporine for prevention of graft-versus-host disease after allogeneic bone marrow transplantation from HLA allele-matched, unrelated donors. Int J Hematol. 2006;83:159–63.

    Article  CAS  PubMed  Google Scholar 

  20. Ogawa N, Kanda Y, Matsubara M, Asano Y, Nakagawa M, Sakata-Yanagimoto M, et al. Increased incidence of acute graft-versus-host disease with the continuous infusion of cyclosporine A compared to twice-daily infusion. Bone Marrow Transpl. 2004;33:549–52.

    Article  CAS  Google Scholar 

  21. Kanda Y, Hyo R, Yamashita T, Fujimaki K, Oshima K, Onoda M, Mori T, Sakura T, Tanaka M, Sakai M, Taguchi J, Kurakawa M, Maruta A, Okamoto S, Sakamaki H, Kanto Study Group of Cell Therapy. Effect of blood cyclosporine concentration on the outcome of hematopoietic stem cell transplantation from an HLA-matched sibling donor. Am J Hematol. 2006;81(11):838–44.

    Article  Google Scholar 

  22. Oshima K, Kanda Y, Nakasone H, Arai S, Nishimoto N, Sato H, et al. Decreased incidence of acute graft-versus-host disease by continuous infusion of cyclosporine with a higher target blood level. Am J Hematol. 2008;83:226–32.

    Article  CAS  PubMed  Google Scholar 

  23. International Neoral Renal Transplantation Study Group. Cyclosporine microemulsion (Neoral) absorption profiling and sparse-sample predictors during the first 3 months after renal transplantation. Am J Transpl. 2002;2:148–56.

    Article  Google Scholar 

Download references

Acknowledgments

We thank Miyako Baba and Yoko Tanahashi, Clinical Laboratory Division, Niigata University Medical and Dental Hospital for their excellent technical assistance and helpful discussions.

Author information

Authors and Affiliations

  1. Division of Bone Marrow Transplantation, Niigata University Medical and Dental Hospital, Asahimachi-dori 1-754, Chuoku, Niigata, 951-8520, Japan

    Tatsuo Furukawa & Masayoshi Masuko

  2. Division of Hematology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

    Tori Kurasaki-Ida, Nobuhiro Tsukada, Kiyoshi Okazuka, Toshio Yano, Takashi Abe, Akihito Momoi, Yasuhiko Shibasaki, Masutaka Higashimura, Kaori Karimata, Masato Moriyama, Takashi Kuroha, Jun Takizawa, Ken Toba & Yoshifusa Aizawa

  3. Nagaoka Red Cross Hospital, Nagaoka, Japan

    Naoko Sato

  4. Laboratory of Hematology and Oncology, Graduate School of Health Sciences, Niigata University, Niigata, Japan

    Miwako Narita & Masuhiro Takahashi

  5. Regeneration, Transfusion and Transplantation Division, Bioscience Medical Research Center, Niigata University Medical and Dental Hospital, Niigata, Japan

    Ichiro Fuse

Authors
  1. Tatsuo Furukawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tori Kurasaki-Ida
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Masayoshi Masuko
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nobuhiro Tsukada
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kiyoshi Okazuka
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Naoko Sato
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Toshio Yano
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Takashi Abe
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Akihito Momoi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yasuhiko Shibasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Masutaka Higashimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Kaori Karimata
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Masato Moriyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Takashi Kuroha
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Jun Takizawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Ken Toba
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Miwako Narita
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Ichiro Fuse
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Masuhiro Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Yoshifusa Aizawa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tatsuo Furukawa.

About this article

Cite this article

Furukawa, T., Kurasaki-Ida, T., Masuko, M. et al. Pharmacokinetic and pharmacodynamic analysis of cyclosporine A (CsA) to find the best single time point for the monitoring and adjusting of CsA dose using twice-daily 3-h intravenous infusions in allogeneic hematopoietic stem cell transplantation. Int J Hematol 92, 144–151 (2010). https://doi.org/10.1007/s12185-010-0610-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-010-0610-0

Keywords

Search

Navigation