Skip to main content

Advertisement

SpringerLink
Log in

Influence of Dosing Schedule on Organ Exposure to Cyclosporin in Pediatric Hematopoietic Stem Cell Transplantation: Analysis with a PBPK Model

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

ABSTRACT

Purpose

Cyclosporin is administered by intermittent infusions (II) or continuous infusions (CI) to prevent acute graft-versus-host disease (aGVHD). Because cyclosporin disposition is nonlinear, organ exposure may be higher after II than after CI, but saturation of receptors must be accounted for. The aim of the study was to compare both types of administration using a mechanistic model.

Methods

A physiologically based pharmacokinetic model was developed to estimate cyclosporin exposure and receptor occupancies (RO) in aGVHD target organs and kidneys and to compare these estimations in pediatric patients that received cyclosporin either by II or CI. The relevant biological parameters were based on a clinical study in 2 groups of pediatric patients that received cyclosporin either by II (n = 31) or CI (n = 30).

Results

Simulations showed that the exposure to cyclosporin in the interstitial fluid of aGVHD target organs was greater at day 1 after II than after CI. In kidneys, the opposite order was observed. AUCRO in all organs was greater after CI than after II. The therapeutic index (the ratio of AUCRO in blood to AUCRO in kidneys) was greater with CI than with II.

Conclusions

CI may be slightly more favorable than II for aGVHD prevention.

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
Fig. 5
Fig. 6

Similar content being viewed by others

REFERENCES

  1. Welniak LA, Blazar BR, Murphy WJ. Immunobiology of allogeneic hematopoietic stem cell transplantation. Annu Rev Immunol. 2007;25:139–70.

    Article  CAS  PubMed  Google Scholar 

  2. Appelbaum FR. Haematopoietic cell transplantation as immunotherapy. Nature. 2001;411:385–9.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  4. Bowers LD. Therapeutic monitoring for cyclosporine: difficulties in establishing a therapeutic window. Clin Biochem. 1991;24:81–7.

    Article  CAS  PubMed  Google Scholar 

  5. 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.

    Article  CAS  PubMed  Google Scholar 

  6. 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.

    Article  CAS  PubMed  Google Scholar 

  7. Yee GC, Self SG, McGuire TR, Carlin J, Sanders JE, Deeg HJ. Serum cyclosporine concentration and risk of acute graft-versus-host disease after allogeneic marrow transplantation. N Engl J Med. 1988;319:65–70.

    Article  CAS  PubMed  Google Scholar 

  8. Przepiorka D, Shapiro S, Schwinghammer TL, Bloom EJ, Rosenfeld CS, Shadduck RK, et al. Cyclosporine and methylprednisolone after allogeneic marrow transplantation: association between low cyclosporine concentration and risk of acute graft-versus-host disease. Bone Marrow Transplant. 1991;7:461–5.

    CAS  PubMed  Google Scholar 

  9. Ghalie R, Fitzsimmons WE, Weinstein A, Manson S, Kaizer H. Cyclosporine monitoring improves graft-versus-host disease prophylaxis after bone marrow transplantation. Ann Pharmacother. 1994;28:379–83.

    CAS  PubMed  Google Scholar 

  10. Eisner MD, August CS. Impact of donor and recipient characteristics on the development of acute and chronic graft-versus-host disease following pediatric bone marrow transplantation. Bone Marrow Transplant. 1995;15:663–8.

    CAS  PubMed  Google Scholar 

  11. 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.

    Article  CAS  PubMed  Google Scholar 

  12. 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.

    Article  CAS  PubMed  Google Scholar 

  13. 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.

    Article  CAS  PubMed  Google Scholar 

  14. 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.

    Article  CAS  PubMed  Google Scholar 

  15. 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.

    Article  CAS  PubMed  Google Scholar 

  16. Tanaka C, Kawai R, Rowland M. Physiologically based pharmacokinetics of cyclosporine A: reevaluation of dose-nonlinear kinetics in rats. J Pharmacokinet Biopharm. 1999;27:597–623.

    Article  CAS  PubMed  Google Scholar 

  17. Kawai R, Mathew D, Tanaka C, Rowland M. Physiologically based pharmacokinetics of cyclosporine A: extension to tissue distribution kinetics in rats and scale-up to human. J Pharmacol Exp Ther. 1998;287:457–68.

    CAS  PubMed  Google Scholar 

  18. Dartois C, Freyer G, Michallet M, Henin E, You B, Darlavoix I, et al. Exposure-effect population model of inolimomab, a monoclonal antibody administered in first-line treatment for acute graft-versus-host disease. Clin Pharmacokinet. 2007;46:417–32.

    Article  CAS  PubMed  Google Scholar 

  19. Bernareggi A, Rowland M. Physiologic modeling of cyclosporin kinetics in rat and man. J Pharmacokinet Biopharm. 1991;19:21–50.

    Article  CAS  PubMed  Google Scholar 

  20. Kawai R, Lemaire M. Role of blood cell uptake on cyclosporin pharmacokinetics. In: Tillement P, Eckert H, editors. Proceeding of the International Symosium on Blood Binding and Drug Transfer. Paris: EFC; 1993. p. 89–108.

    Google Scholar 

  21. Brown RP, Delp MD, Lindstedt SL, Rhomberg LR, Beliles RP. Physiological parameter values for physiologically based pharmacokinetic models. Toxicol Ind Health. 1997;13:407–84.

    CAS  PubMed  Google Scholar 

  22. Niederberger W, Lemaire M, Maurer G, Nussbaumer K, Wagner O. Distribution and binding of cyclosporin in blood and tissues. Transplant Proc. 1983;15:2419–21.

    CAS  Google Scholar 

  23. Kawai R, Lemaire M, Steimer JL, Bruelisauer A, Niederberger W, Rowland M. Physiologically based pharmacokinetic study on a cyclosporin derivative, SDZ IMM 125. J Pharmacokinet Biopharm. 1994;22:327–65.

    Article  CAS  PubMed  Google Scholar 

  24. Wagner O, Schreier E, Heitz F, Maurer G. Tissue distribution, disposition, and metabolism of cyclosporine in rats. Drug Metab Dispos. 1987;15:377–83.

    CAS  PubMed  Google Scholar 

  25. Kelly P, Kahan BD. Review: metabolism of immunosuppressant drugs. Curr Drug Metab. 2002;3:275–87.

    Article  CAS  PubMed  Google Scholar 

  26. D’Argenio D, Schumitzky A. ADAPT II User’s guide. Pharmacokinetic/Pharmacodynamic Systems Analysis Software. Los Angeles: Biomedical Simulations Ressource; 1997.

    Google Scholar 

  27. Anderson BJ, Holford NH. Mechanism-based concepts of size and maturity in pharmacokinetics. Annu Rev Pharmacol Toxicol. 2008;48:303–32.

    Article  CAS  PubMed  Google Scholar 

  28. Bjorkman S. Prediction of drug disposition in infants and children by means of physiologically based pharmacokinetic (PBPK) modelling: theophylline and midazolam as model drugs. Br J Clin Pharmacol. 2005;59:691–704.

    Article  PubMed  Google Scholar 

  29. Edginton AN, Schmitt W, Willmann S. Development and evaluation of a generic physiologically based pharmacokinetic model for children. Clin Pharmacokinet. 2006;45:1013–34.

    Article  CAS  PubMed  Google Scholar 

  30. Legg B, Gupta SK, Rowland M. A model to account for the variation in cyclosporin binding to plasma lipids in transplant patients. Ther Drug Monit. 1988;10:20–7.

    CAS  PubMed  Google Scholar 

  31. National Cholesterol Education Program (NCEP). highlights of the report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents. Pediatrics. 1992;89:495–501.

    Google Scholar 

  32. Girardet J-P. Management of children with hypercholesterolemia. Pédiatrie. 2006;13:104–10.

    Article  Google Scholar 

  33. Johnson TN, Rostami-Hodjegan A, Tucker GT. Prediction of the clearance of eleven drugs and associated variability in neonates, infants and children. Clin Pharmacokinet. 2006;45:931–56.

    Article  CAS  PubMed  Google Scholar 

  34. Wong SH. Therapeutic drug monitoring for immunosuppressants. Clin Chim Acta. 2001;313:241–53.

    Article  CAS  PubMed  Google Scholar 

  35. Stein CM, Murray JJ, Wood AJ. Inhibition of stimulated interleukin-2 production in whole blood: a practical measure of cyclosporine effect. Clin Chem. 1999;45:1477–84.

    CAS  PubMed  Google Scholar 

  36. Marshall JD, Kearns GL. Developmental pharmacodynamics of cyclosporine. Clin Pharmacol Ther. 1999;66:66–75.

    Article  CAS  PubMed  Google Scholar 

  37. Caruso R, Perico N, Cattaneo D, Piccinini G, Bonazzola S, Remuzzi G, et al. Whole-blood calcineurin activity is not predicted by cyclosporine blood concentration in renal transplant recipients. Clin Chem. 2001;47:1679–87.

    CAS  PubMed  Google Scholar 

  38. Barama A, Perner F, Beauregard-Zollinger L. Absorption profiling of cyclosporine therapy for de novo kidney transplantation: a retrospective randomized study comparing sparse sampling to trough monitoring [abstract no. 190]. Transplantation. 2000;69(Suppl):S162.

    Google Scholar 

  39. Keown PA. New concepts in cyclosporine monitoring. Curr Opin Nephrol Hypertens. 2002;11:619–26.

    Article  PubMed  Google Scholar 

  40. Lanino E, Rondelli R, Locatelli F, Messina C, Pession A, Balduzzi A, et al. Early (day -7) versus conventional (day -1) inception of cyclosporine-A for graft-versus-host disease prophylaxis after unrelated donor hematopoietic stem cell transplantation in children. Long-term results of an AIEOP prospective, randomized study. Biol Blood Marrow Transplant. 2009;15:741–8.

    Article  CAS  PubMed  Google Scholar 

  41. Dini G, Lamparelli T, Rondelli R, Lanino E, Barbanti M, Costa C, et al. Unrelated donor marrow transplantation for chronic myelogenous leukaemia. Br J Haematol. 1998;102:544–52.

    Article  CAS  PubMed  Google Scholar 

  42. Busauschina A, Schnuelle P, van der Woude FJ. Cyclosporine nephrotoxicity. Transplant Proc. 2004;36:229S–33S.

    Article  CAS  PubMed  Google Scholar 

Download references

ACKNOWLEDGEMENTS

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Author information

Authors and Affiliations

  1. Université de Lyon, Lyon, F-69003, France

    Cécile Gérard, Pascal Girard, Gilles Freyer & Michel Tod

  2. Faculté de Médecine Lyon Sud, Université Lyon 1, EA3738, CTO, Oullins, F-69600, France

    Cécile Gérard, Pascal Girard, Gilles Freyer & Michel Tod

  3. Institut d’Hématologie et d’Oncologie Pédiatrique, Lyon, France

    Nathalie Bleyzac & Yves Bertrand

  4. Faculté de Médecine, Université Lyon 1, CNRS UMR5558, Lyon, F-69008, France

    Nathalie Bleyzac

  5. Pharmacie, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, 103 Grande rue de la Croix-Rousse, 69317, Lyon cedex 04, France

    Michel Tod

Authors
  1. Cécile Gérard
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nathalie Bleyzac
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pascal Girard
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gilles Freyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yves Bertrand
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michel Tod
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michel Tod.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gérard, C., Bleyzac, N., Girard, P. et al. Influence of Dosing Schedule on Organ Exposure to Cyclosporin in Pediatric Hematopoietic Stem Cell Transplantation: Analysis with a PBPK Model. Pharm Res 27, 2602–2613 (2010). https://doi.org/10.1007/s11095-010-0252-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-010-0252-1

KEY WORDS

Search

Navigation