Skip to main content

Advertisement

SpringerLink
Log in

Pharmacokinetic comparison of cyclosporin A and tacrolimus in graft-versus-host disease prophylaxis

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

Abstract

A number of studies were published with contradictory results comparing tacrolimus (Tac) and cyclosporine A (CsA) for graft-versus-host disease (GVHD) prophylaxis, but there are only few that accounted for pharmacokinetic (PK) parameters. In this study, we created a model based on median concentrations, variability of concentrations, and failures to maintain target levels that distinguished patients with low, intermediate, and high risks of acute GVHD (hazard ratios (HR) 1.77, 95%CI 1.36–2.32, p < 0.0001). This model was used to compare 95 patients with CsA and 239 with Tac GVHD prophylaxis. In the multivariate analysis, incorporating PK risk, no differences were observed for grade II–IV acute GVHD (HR 0.73, 95%CI 0.48–1.10, p = 0.13), but grade III–IV acute GVHD was lower in the Tac group (HR 0.47, 95%CI 0.28–0.78, p = 0.004). The observed difference was due to patients with high PK risk (HR 0.377, 95%CI 0.19–0.75, p = 0.005), but not with low and intermediate PK risk (p > 0.05). Patients in the Tac group had better GVHD relapse-free survival (HR = 0.659, p = 0.01) and comparable overall survival (p > 0.05). In conclusion, PK risk should be accounted for in comparisons of GVHD prophylaxis regimens with calcineurin inhibitors, and Tac was superior to CsA in patients with high, but not intermediate and low PK risk.

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. Storb R, Deeg HJ, Farewell V et al (1986) Marrow transplantation for severe aplastic anemia: methotrexate alone compared with a combination of methotrexate and cyclosporine for prevention of acute graft-versus-host disease. Blood 68:119–125

    CAS  PubMed  Google Scholar 

  2. Ruutu T, van Biezen A, Hertenstein B et al (2012) Prophylaxis and treatment of GVHD after allogeneic haematopoietic SCT: a survey of centre strategies by the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant 47(11):1459–1464

    Article  CAS  PubMed  Google Scholar 

  3. Fay JW, Wingard JR, Antin JH et al (1996) FK506 (tacrolimus) monotherapy for prevention of graft-versus-host disease after histocompatible sibling allogenic bone marrow transplantation. Blood 87(8):3514–3519

    CAS  PubMed  Google Scholar 

  4. Uberti JP, Silver SM, Adams PT, Jacobson P, Scalzo A, Ratanatharathorn V (1997) Tacrolimus and methotrexate for the prophylaxis of acute graft-versus-host disease in allogeneic bone marrow transplantation in patients with hematologic malignancies. Bone Marrow Transplant 19(12):1233–1238

    Article  CAS  PubMed  Google Scholar 

  5. Ratanatharathorn V, Nash RA, Przepiorka D et al (1998) Phase III study comparing methotrexate and tacrolimus (prograf, FK506) with methotrexate and cyclosporine for graft-versus-host disease prophylaxis after HLA-identical sibling bone marrow transplantation. Blood 92(7):2303–2314

    CAS  PubMed  Google Scholar 

  6. Hiraoka A, Ohashi Y, Okamoto S et al (2001) Phase III study comparing tacrolimus (FK506) with cyclosporine for graft-versus-host disease prophylaxis after allogeneic bone marrow transplantation. Bone Marrow Transplant 28(2):181–185

    Article  CAS  PubMed  Google Scholar 

  7. Inamoto Y, Flowers ME, Appelbaum FR et al (2011) A retrospective comparison of tacrolimus versus cyclosporine with methotrexate for immunosuppression after allogeneic hematopoietic cell transplantation with mobilized blood cells. Biol Blood Marrow Transplant 17(7):1088–1092

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Yanada M, Emi N, Naoe T et al (2004) Tacrolimus instead of cyclosporine used for prophylaxis against graft-versus-host disease improves outcome after hematopoietic stem cell transplantation from unrelated donors, but not from HLA-identical sibling donors: a nationwide survey conducted in Japan. Bone Marrow Transplant 34(4):331–337

    Article  CAS  PubMed  Google Scholar 

  9. Martin P, Bleyzac N, Souillet G et al (2003) Relationship between CsA trough blood concentration and severity of acute graft-versus-host disease after paediatric stem cell transplantation from matched-sibling or unrelated donors. Bone Marrow Transplant 32(8):777–784

    Article  CAS  PubMed  Google Scholar 

  10. Ganetsky A, Shah A, Miano TA et al (2016) Higher tacrolimus concentrations early after transplant reduce the risk of acute GvHD in reduced-intensity allogeneic stem cell transplantation. Bone Marrow Transplant 51(4):568–572

    Article  CAS  PubMed  Google Scholar 

  11. Mori T, Kato J, Shimizu T et al (2012) Effect of early posttransplantation tacrolimus concentration on the development of acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation from unrelated donors. Biol Blood Marrow Transplant 18(2):229–234

    Article  CAS  PubMed  Google Scholar 

  12. Kanda Y, Kobayashi T, Mori T et al (2016) A randomized controlled trial of cyclosporine and tacrolimus with strict control of blood concentrations after unrelated bone marrow transplantation. Bone Marrow Transplant 51(1):103–109

    Article  CAS  PubMed  Google Scholar 

  13. Luznik L, O’Donnell PV, Symons HJ et al (2008) HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant 14(6):641–650

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Mehta RS, Saliba RM, Chen J et al (2016) Post-transplantation cyclophosphamide versus conventional graft-versus-host disease prophylaxis in mismatched unrelated donor haematopoietic cell transplantation. Br J Haematol 173(3):444–455

    Article  CAS  PubMed  Google Scholar 

  15. Maschan M, Shelikhova L, Ilushina M et al (2016) TCR-alpha/beta and CD19 depletion and treosulfan-based conditioning regimen in unrelated and haploidentical transplantation in children with acute myeloid leukemia. Bone Marrow Transplant 51(5):668–674

    Article  CAS  PubMed  Google Scholar 

  16. Holtick U, Chemnitz JM, Shimabukuro-Vornhagen A et al (2016) OCTET-CY: a phase II study to investigate the efficacy of post-transplant cyclophosphamide as sole graft-versus-host prophylaxis after allogeneic peripheral blood stem cell transplantation. Eur J Haematol 96(1):27–35

    Article  CAS  PubMed  Google Scholar 

  17. Tutschka PJ, Copelan EA, Klein JP (1987) Bone marrow transplantation for leukemia following a new busulfan and cyclophosphamide regimen. Blood 70(5):1382–1388

    CAS  PubMed  Google Scholar 

  18. Nagler A, Aker M, Or R et al (2001) Low-intensity conditioning is sufficient to ensure engraftment in matched unrelated bone marrow transplantation. Exp Hematol 29(3):362–370

    Article  CAS  PubMed  Google Scholar 

  19. Bacigalupo A, Locatelli F, Lanino E et al (2005) Fludarabine, cyclophosphamide and anti-thymocyte globulin for alternative donor transplants in acquired severe aplastic anemia: a report from the EBMT-SAA Working Party. Bone Marrow Transplant 36(11):947–950

    Article  CAS  PubMed  Google Scholar 

  20. Holtan SG, DeFor TE, Lazaryan A et al (2015) Composite end point of graft-versus-host disease-free, relapse-free survival after allogeneic hematopoietic cell transplantation. Blood 125(8):1333–1338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Przepiorka D, Weisdorf D, Martin P et al (1995) 1994 Consensus conference on acute GVHD grading. Bone Marrow Transplant 15(6):825–828

    CAS  PubMed  Google Scholar 

  22. Filipovich AH, Weisdorf D, Pavletic S et al (2005) National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 11(12):945–956

    Article  PubMed  Google Scholar 

  23. Dellinger RP, Levy MM, Rhodes A et al (2013) Surviving sepsis campaign: International Guidelines for Management of Severe Sepsis and Septic Shock, 2012. Intensive Care Med 39(2):165–228

    Article  CAS  PubMed  Google Scholar 

  24. De Pauw B, Walsh TJ, Donnelly JP et al (2008) Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis 46(12):1813–1821

    Article  PubMed  PubMed Central  Google Scholar 

  25. McDonald GB, Hinds MS, Fisher LD et al (1993) Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients. Ann Intern Med 118(4):255–267

    Article  CAS  PubMed  Google Scholar 

  26. Cho BS, Yahng SA, Lee SE, Eom KS, Kim YJ, Kim HJ (2010) Validation of recently proposed consensus criteria for thrombotic microangiopathy after allogeneic hematopoietic stem-cell transplantation. Transplantation 90(8):918–926

    Article  CAS  PubMed  Google Scholar 

  27. Gooley TA, Leisenring W, Crowley J, Storer BE (1999) Estimation of failure probabilities in the presence of competing risks: new representation of old estimators. Stat Med 18(6):695–706

    Article  CAS  PubMed  Google Scholar 

  28. Lin G, So Y, Johnston G (2012) Analyzing survival data with competing risks using SAS software, Proceedings of the SAS Global Forum 2012 Conference. SAS Global Forum. Vol. 2102. SAS Institute Inc, Cary

    Google Scholar 

  29. Pollock-Barziv SM, Finkelstein Y, Manlhiot C et al (2010) Variability in tacrolimus blood levels increases the risk of late rejection and graft loss after solid organ transplantation in older children. Pediatr Transplant 14(8):968–975

    Article  PubMed  Google Scholar 

  30. Huang CT, Shu KH, Ho HC, Wu MJ (2016) Higher variability of tacrolimus trough level increases risk of acute rejection in kidney transplant recipients. Transplant Proc 48(6):1978–1980

    Article  CAS  PubMed  Google Scholar 

  31. Pizzo HP, Ettenger RB, Gjertson DW et al. Sirolimus and tacrolimus coefficient of variation is associated with rejection, donor-specific antibodies, and nonadherence. Pediatr Nephrol. 2016 Jun 10

  32. Kohnert KD, Heinke P, Fritzsche G, Vogt L, Augstein P, Salzsieder E (2013) Evaluation of the mean absolute glucose change as a measure of glycemic variability using continuous glucose monitoring data. Diabetes Technol Ther 15(6):448–454

    Article  CAS  PubMed  Google Scholar 

  33. Mori T, Aisa Y, Kato J, Nakamura Y, Ikeda Y, Okamoto S (2009) Drug interaction between voriconazole and calcineurin inhibitors in allogeneic hematopoietic stem cell transplant recipients. Bone Marrow Transplant 44(6):371–374

    Article  CAS  PubMed  Google Scholar 

  34. Mihara A, Mori T, Aisa Y et al (2008) Greater impact of oral fluconazole on drug interaction with intravenous calcineurin inhibitors as compared with intravenous fluconazole. Eur J Clin Pharmacol 64(1):89–91

    Article  CAS  PubMed  Google Scholar 

  35. Mori T, Aisa Y, Nakazato T, Yamazaki R, Ikeda Y, Okamoto S (2005) Tacrolimus-azithromycin interaction in a recipient of allogeneic bone marrow transplantation. Transpl Int 18(6):757–758

    Article  PubMed  Google Scholar 

  36. Page RL, Klem PM, Rogers C (2005) Potential elevation of tacrolimus trough concentrations with concomitant metronidazole therapy. Ann Pharmacother 39(6):1109–1113

    Article  PubMed  Google Scholar 

  37. Bernard E, Goutelle S, Bertrand Y, Bleyzac N (2014) Pharmacokinetic drug-drug interaction of calcium channel blockers with cyclosporine in hematopoietic stem cell transplant children. Ann Pharmacother 48(12):1580–1584

    Article  PubMed  Google Scholar 

  38. Bleyzac N, Kebaili K, Mialou V, Bertrand Y, Goutelle S (2014) Pharmacokinetic drug interaction between cyclosporine and imatinib in bone marrow transplant children and model-based reappraisal of imatinib drug interaction profile. Ther Drug Monit 36(6):724–729

    Article  CAS  PubMed  Google Scholar 

  39. Aoudjhane M, Labopin M, Gorin NC et al (2005) Comparative outcome of reduced intensity and myeloablative conditioning regimen in HLA identical sibling allogeneic haematopoietic stem cell transplantation for patients older than 50 years of age with acute myeloblastic leukaemia: a retrospective survey from the Acute Leukemia Working Party (ALWP) of the European Group for Blood and Marrow Transplantation (EBMT). Leukemia 19(12):2304–2312

  40. Crawley C, Szydlo R, Lalancette M et al (2005) Outcomes of reduced-intensity transplantation for chronic myeloid leukemia: an analysis of prognostic factors from the Chronic Leukemia Working Party of the EBMT. Blood 106(9):2969–2976

    Article  CAS  PubMed  Google Scholar 

  41. Kuypers DR, Claes K, Evenepoel P, Maes B, Vanrenterghem Y (2004) Clinical efficacy and toxicity profile of tacrolimus and mycophenolic acid in relation to combined long-term pharmacokinetics in de novo renal allograft recipients. Clin Pharmacol Ther 75(5):434–447

    Article  CAS  PubMed  Google Scholar 

  42. Keown P, Landsberg D, Halloran P et al (1996) A randomized, prospective multicenter pharmacoepidemiologic study of cyclosporine microemulsion in stable renal graft recipients. Report of the Canadian Neoral Renal Transplantation Study Group. Transplantation 62(12):1744–1752

    Article  CAS  PubMed  Google Scholar 

  43. Kuypers DR, de Jonge H, Naesens M, Lerut E, Verbeke K, Vanrenterghem Y (2007) CYP3A5 and CYP3A4 but not MDR1 single-nucleotide polymorphisms determine long-term tacrolimus disposition and drug-related nephrotoxicity in renal recipients. Clin Pharmacol Ther 82(6):711–725

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The reported study was supported by The Russian Foundation for Basic Research, according to the research project no. 16-34-60142 mol_а_dk.

Author information

Authors and Affiliations

  1. R.M.Gorbacheva Memorial Institute of Oncology, Hematology and Transplantation, Pavlov First Saint Petersburg State Medical University, Saint Petersburg, Russia

    Ivan Sergeevich Moiseev, Ekaterina Andreevna Burmina, Albert Radikovich Muslimov, Olga Vladislavovna Pirogova, Sergey Nikolaevich Bondarenko, Elena Igorevna Darskaya, Yuliya Alexandrovna Tarakanova, Nadegda Georgievna Senina & Boris Vladimirovich Afanasyev

Authors
  1. Ivan Sergeevich Moiseev
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ekaterina Andreevna Burmina
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Albert Radikovich Muslimov
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Olga Vladislavovna Pirogova
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sergey Nikolaevich Bondarenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Elena Igorevna Darskaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yuliya Alexandrovna Tarakanova
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Nadegda Georgievna Senina
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Boris Vladimirovich Afanasyev
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ivan Sergeevich Moiseev.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Moiseev, I.S., Burmina, E.A., Muslimov, A.R. et al. Pharmacokinetic comparison of cyclosporin A and tacrolimus in graft-versus-host disease prophylaxis. Ann Hematol 96, 935–942 (2017). https://doi.org/10.1007/s00277-017-2975-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00277-017-2975-0

Keywords

Search

Navigation