Pharmaceutical Research

, Volume 28, Issue 3, pp 531–539 | Cite as

Links Between Cyclosporin Exposure in Tissues and Graft-Versus-Host Disease in Pediatric Bone Marrow Transplantation: Analysis by a PBPK Model

  • Cécile Gérard
  • Nathalie Bleyzac
  • Pascal Girard
  • Gilles Freyer
  • Yves Bertrand
  • Michel Tod
Research Paper

ABSTRACT

Purpose

In hematopoietic stem cell transplantation (HSCT), cyclosporin is used to prevent graft-versus-host disease (GVHD). However, cyclosporin distribution in tissues is not linear, resulting in uncertainty regarding optimal dosing and monitoring. The objective of this study was to link the probability and severity of acute GVHD to cyclosporin exposure in blood, GVHD target organs, and lymphoid organs.

Methods

A physiologically based pharmacokinetic model of cyclosporin disposition and logistic regression models were used. Sixty-one pediatric patients undergoing HSCT were studied. Cyclosporin was administered by intermittent (n = 31) or continuous infusion (n = 30).

Results

At steady state (1 day before acute GVHD), exposures in all organs were related with the probability and severity of acute GVHD. Average cyclosporin concentration or, equivalently, its area under the curve (AUC) was the pharmacokinetic index best correlated with the anti-GVHD effect. Cyclosporin AUC in interstitial fluid of lymphoid organs was a superior index than that in blood, but marginally.

Conclusion

Hence, AUC in blood maybe used as an index of cyclosporin efficacy. Using our model, target AUCs in blood could be defined for malignant and non-malignant diseases, as well as the equivalent target values for C2 and C0 concentrations.

KEY WORDS

bone marrow transplantation cyclosporin GVHD PBPK modelling 

REFERENCES

  1. 1.
    Ferrara JL, Levine JE, Reddy P, Holler E. Graft-versus-host disease. Lancet. 2009;373:1550–61.CrossRefPubMedGoogle Scholar
  2. 2.
    Appelbaum FR. Haematopoietic cell transplantation as immunotherapy. Nature. 2001;411:385–9.CrossRefPubMedGoogle Scholar
  3. 3.
    Bowers LD. Therapeutic monitoring for cyclosporine: difficulties in establishing a therapeutic window. Clin Biochem. 1991;24:81–7.CrossRefPubMedGoogle Scholar
  4. 4.
    Martin P, Bleyzac N, Souillet G, Galambrun C, Bertrand Y, Maire PH, et al. 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. 2003;32:777–84.CrossRefPubMedGoogle Scholar
  5. 5.
    Byrne JL, Stainer C, Hyde H, Miflin G, Haynes AP, Bessell EM, et al. Low incidence of acute graft-versus-host disease and recurrent leukaemia in patients undergoing allogeneic haemopoietic stem cell transplantation from sibling donors with methotrexate and dose-monitored cyclosporin A prophylaxis. Bone Marrow Transplant. 1998;22:541–5.CrossRefPubMedGoogle Scholar
  6. 6.
    Carlens S, Aschan J, Remberger M, Dilber M, Ringden O. Low-dose cyclosporine of short duration increases the risk of mild and moderate GVHD and reduces the risk of relapse in HLA-identical sibling marrow transplant recipients with leukaemia. Bone Marrow Transplant. 1999;24:629–35.CrossRefPubMedGoogle Scholar
  7. 7.
    Cahn JY, Klein JP, Lee SJ, Milpied N, Blaise D, Antin JH, et al. Prospective evaluation of 2 acute graft-versus-host (GVHD) grading systems: a joint Societe Francaise de Greffe de Moelle et Therapie Cellulaire (SFGM-TC), Dana Farber Cancer Institute (DFCI), and International Bone Marrow Transplant Registry (IBMTR) prospective study. Blood. 2005;106:1495–500.CrossRefPubMedGoogle Scholar
  8. 8.
    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 Transplant. 1997;19:759–64.CrossRefPubMedGoogle Scholar
  9. 9.
    Gerard C, Bleyzac N, Girard P, Freyer G, Bertrand Y, Tod M. Influence of dosing schedule on organ exposure to cyclosporin in pediatric hematopoietic stem cell transplantation: analysis with a PBPK-PD model. Pharm Res. 2010. doi:10.1007/s11095-010-0252-1.
  10. 10.
    Morris RG, Russ GR, Cervelli MJ, Juneja R, McDonald SP, Mathew TH. Comparison of trough, 2-hour, and limited AUC blood sampling for monitoring cyclosporin (Neoral) at day 7 post-renal transplantation and incidence of rejection in the first month. Ther Drug Monit. 2002;24:479–86.CrossRefPubMedGoogle Scholar
  11. 11.
    Pescovitzand MD, Barbeito R. Two-hour post-dose cyclosporine level is a better predictor than trough level of acute rejection of renal allografts. Clin Transplant. 2002;16:378–82.CrossRefGoogle Scholar
  12. 12.
    Caforio AL, Tona F, Piaserico S, Gambino A, Feltrin G, Fortina AB, et al. C2 is superior to C0 as predictor of renal toxicity and rejection risk profile in stable heart transplant recipients. Transpl Int. 2005;18:116–24.CrossRefPubMedGoogle Scholar
  13. 13.
    Li J, Dahmen U, Beckebaum S, Cicinnati V, Valentin-Gamazo C, Frilling A, et al. Target range maximum of cyclosporine blood concentration two hours post dose in stable liver transplant patients. Eur J Med Res. 2006;11:139–45.PubMedGoogle Scholar
  14. 14.
    Rodrigo E, Ruiz JC, Angeles de Cos M, Ruiz J, Gago M, Pinera C, et al. Correlation of C0 and C2 levels with cyclosporine side effects in kidney transplantation. Transplant Proc. 2009;41:2328–31.CrossRefPubMedGoogle Scholar
  15. 15.
    Troncoso P, Ortiz AM, Jara A, Vilches S. Abbreviated AUC monitoring of cyclosporine more adequately identified patients at risk for acute rejection during induction of immunosuppressive therapy after kidney transplantation than recommended C2 concentration values. Transplant Proc. 2009;41:127–30.CrossRefPubMedGoogle Scholar
  16. 16.
    Barkholt L, Remberger M, Bodegard H, Ringden O, Bottiger Y. Cyclosporine A (CsA) 2-h concentrations vary between patients without correlation to graft-versus-host disease after allogeneic haematopoietic stem cell transplantation. Bone Marrow Transplant. 2007;40:683–9.CrossRefPubMedGoogle Scholar
  17. 17.
    Punnett A, Sung L, Price V, Das P, Diezi M, Doyle J, et al. Achievement of target cyclosporine concentrations as a predictor of severe acute graft versus host disease in children undergoing hematopoietic stem cell transplantation and receiving cyclosporine and methotrexate prophylaxis. Ther Drug Monit. 2007;29:750–7.CrossRefPubMedGoogle Scholar
  18. 18.
    Sibbald C, Seto W, Taylor T, Saunders EF, Doyle J, Dupuis LL. Determination of area under the whole blood concentration versus time curve after first intravenous cyclosporine dose in children undergoing hematopoietic stem cell transplant: limited sampling strategies. Ther Drug Monit. 2008;30:434–8.PubMedGoogle Scholar
  19. 19.
    Martin P, Bleyzac N, Souillet G, Galambrun C, Bertrand Y, Maire PH, et al. Clinical and pharmacological risk factors for acute graft-versus-host disease after paediatric bone marrow transplantation from matched-sibling or unrelated donors. Bone Marrow Transplant. 2003;32:881–7.CrossRefPubMedGoogle Scholar
  20. 20.
    Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA, et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation. 1974;18:295–304.CrossRefPubMedGoogle Scholar
  21. 21.
    Armitage JO. Bone marrow transplantation. N Engl J Med. 1994;330:827–38.CrossRefPubMedGoogle Scholar
  22. 22.
    Michallet M, Dhedin N, Michallet AS. Allogeneic hematopoietic stem-cell transplantation for hematological malignancies. Bull Cancer. 2001;88:908–26.PubMedGoogle Scholar
  23. 23.
    Meille C, Iliadis A, Barbolosi D, Frances N, Freyer G. An interface model for dosage adjustment connects hematotoxicity to pharmacokinetics. J Pharmacokinet Pharmacodyn. 2008;35:619–33.CrossRefPubMedGoogle Scholar
  24. 24.
    Neudorf S, Sanders J, Kobrinsky N, Alonzo TA, Buxton AB, Gold S, et al. Allogeneic bone marrow transplantation for children with acute myelocytic leukemia in first remission demonstrates a role for graft versus leukemia in the maintenance of disease-free survival. Blood. 2004;103:3655–61.CrossRefPubMedGoogle Scholar
  25. 25.
    Miller KB, Schenkein DP, Comenzo R, Erban JK, Fogaren T, Hirsch CA, et al. Adjusted-dose continuous-infusion cyclosporin A to prevent graft-versus-host disease following allogeneic bone marrow transplantation. Ann Hematol. 1994;68:15–20.CrossRefPubMedGoogle Scholar
  26. 26.
    Nash RA, Antin JH, Karanes C, Fay JW, Avalos BR, Yeager AM, et al. Phase 3 study comparing methotrexate and tacrolimus with methotrexate and cyclosporine for prophylaxis of acute graft-versus-host disease after marrow transplantation from unrelated donors. Blood. 2000;96:2062–8.PubMedGoogle Scholar
  27. 27.
    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 Transplant. 2004;33:549–52.CrossRefPubMedGoogle Scholar
  28. 28.
    Hendriks MP, Blijlevens NM, Schattenberg AV, Burger DM, Donnelly JP. Cyclosporine short infusion and C2 monitoring in haematopoietic stem cell transplant recipients. Bone Marrow Transplant. 2006;38:521–5.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Cécile Gérard
    • 1
    • 2
  • Nathalie Bleyzac
    • 3
    • 4
  • Pascal Girard
    • 1
    • 2
  • Gilles Freyer
    • 1
    • 2
  • Yves Bertrand
    • 3
    • 7
  • Michel Tod
    • 1
    • 2
    • 5
    • 6
  1. 1.Université de LyonLyonFrance
  2. 2.Faculté de Médecine Lyon SudUniversité Lyon 1OullinsFrance
  3. 3.Institut d’Hématologie et d’Oncologie PédiatriqueLyonFrance
  4. 4.Faculté de MédecineUniversité Lyon 1LyonFrance
  5. 5.Pharmacie, Hôpital de la Croix-RousseHospices Civils de LyonLyonFrance
  6. 6.PharmacieHôpital de la Croix-RousseLyon cedex 04France
  7. 7.Faculté de Médecine Lyon EstUniversité Lyon 1LyonFrance

Personalised recommendations