Skip to main content
SpringerLink
Log in

The impact of everolimus versus mycophenolate on blood and lymphocyte cyclosporine exposure in heart-transplant recipients

  • Clinical Trial
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Background

Trough- or 2-h post-dose (C2) blood cyclosporine (CsA) concentrations are used for prediction of efficacy and toxicity of CsA in transplant recipients concomitantly treated with antiproliferative agents, but information on utility of blood CsA levels in patients treated with proliferation signal inhibitors (PSIs), such as everolimus, is sparse. Because of the inhibitory effect of PSIs on the P-glycoprotein drug efflux pump present in lymphocytes, we hypothesized that CsA pharmacokinetics in blood and lymphocytes were dissociated in patients concomitantly treated with everolimus.

Methods

Twelve-hour pharmacokinetic studies of whole-blood and intralymphocytic CsA concentrations were conducted in long-term heart-transplant recipients treated with mycophenolate mofetil (MMF) + CsA (n = 8) and everolimus + CsA (n = 9).

Results

There was a highly significant correlation between blood CsA C2 levels and blood CsA AUC0–12 in groups of patients treated with MMF or everolimus (R 2 0.93 and 0.96, respectively; P < 0.001 for both). Whereas blood CsA C2 levels were closely associated with lymphocyte CsA AUC0–12 in patients treated with MMF (R 2 = 0.98), there was poor correlation between whole-blood C2 and lymphocyte AUC0–12 in patients treated with everolimus (R 2 = 0.24).

Conclusion

Standard blood CsA levels accurately predict intralymphocytic exposure to CsA in patients concomitantly treated with MMF but not in patients treated with everolimus.

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

Similar content being viewed by others

References

  1. Taylor DO, Edwards LB, Boucek MM, Trulock EP, Aurora P, Christie J, Dobbels F, Rahmel AO, Keck BM, Hertz MI (2007) Registry of the International Society for Heart and Lung Transplantation: twenty-fourth official adult heart transplant report–2007. J Heart Lung Transplant 26:769–781

    Article  PubMed  Google Scholar 

  2. Alam A, Badovinac K, Ivis F, Trpeski L, Cantarovich M (2007) The outcome of heart transplant recipients following the development of end-stage renal disease: analysis of the Canadian Organ Replacement Register (CORR). Am J Transplant 7:461–465

    Article  PubMed  CAS  Google Scholar 

  3. Angermann CE, Stork S, Costard-Jackle A, Dengler TJ, Siebert U, Tenderich G, Rahmel A, Schwarz ER, Nagele H, Wagner FM, Haaff B, Pethig K (2004) Reduction of cyclosporine after introduction of mycophenolate mofetil improves chronic renal dysfunction in heart transplant recipients–the IMPROVED multi-centre study. Eur Heart J 25:1626–1634

    Article  PubMed  CAS  Google Scholar 

  4. Grant D, Kneteman N, Tchervenkov J, Roy A, Murphy G, Tan A, Hendricks L, Guilbault N, Levy G (1999) Peak cyclosporine levels (Cmax) correlate with freedom from liver graft rejection: results of a prospective, randomized comparison of Neoral and Sandimmune for liver transplantation (NOF-8). Transplantation 67:1133–1137

    Article  PubMed  CAS  Google Scholar 

  5. Cantarovich M, Besner JG, Barkun JS, Elstein E, Loertscher R (1998) Two-hour cyclosporine level determination is the appropriate tool to monitor Neoral therapy. Clin Transplant 12:243–249

    PubMed  CAS  Google Scholar 

  6. Delgado DH, Rao V, Hamel J, Miriuka S, Cusimano RJ, Ross HJ (2005) Monitoring of cyclosporine 2-hour post-dose levels in heart transplantation: improvement in clinical outcomes. J Heart Lung Transplant 24:1343–1346

    Article  PubMed  Google Scholar 

  7. Cantarovich M, Elstein E, de Varennes B, Barkun JS (1999) Clinical benefit of Neoral dose monitoring with cyclosporine 2-hr post-dose levels compared with trough levels in stable heart transplant patients. Transplantation 68:1839–1842

    Article  PubMed  CAS  Google Scholar 

  8. Cantarovich M, Ross H, Arizon JM, Gomez MA, Straatman L, Orus J, Alonso-Pulpon L, Molina BD, Wang S, Lage E, Crespo MG, Manito N, Howlett J, Haddad H (2008) Benefit of Neoral C2 monitoring in de novo cardiac transplant recipients receiving basiliximab induction. Transplantation 85:992–999

    Article  PubMed  CAS  Google Scholar 

  9. Eisen HJ, Tuzcu EM, Dorent R, Kobashigawa J, Mancini D, Valantine-von Kaeppler HA, Starling RC, Sorensen K, Hummel M, Lind JM, Abeywickrama KH, Bernhardt P (2003) Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients. N Engl J Med 349:847–858

    Article  PubMed  CAS  Google Scholar 

  10. Gustafsson F, Ross HJ, Delgado MS, Bernabeo G, Delgado DH (2007) Sirolimus-based immunosuppression after cardiac transplantation: predictors of recovery from calcineurin inhibitor-induced renal dysfunction. J Heart Lung Transplant 26:998–1003

    Article  PubMed  Google Scholar 

  11. Ross H, Pflugfelder P, Haddad H, Cantarovich M, White M, Ignaszewski A, Howlett J, Vaillancourt M, Dorent R, Burton JR (2008) Cyclosporine reduction in the presence of everolimus: 3-month data from a Canadian pilot study of maintenance cardiac allograft recipients. J Heart Lung Transplant 27:197–202

    Article  PubMed  Google Scholar 

  12. Kahan BD, Wong RL, Carter C, Katz SH, Von Fellenberg J, Van Buren CT, Appel-Dingemanse S (1999) A phase I study of a 4-week course of SDZ-RAD (RAD) quiescent cyclosporine-prednisone-treated renal transplant recipients. Transplantation 68:1100–1106

    Article  PubMed  CAS  Google Scholar 

  13. Podder H, Stepkowski SM, Napoli KL, Clark J, Verani RR, Chou TC, Kahan BD (2001) Pharmacokinetic interactions augment toxicities of sirolimus/cyclosporine combinations. J Am Soc Nephrol 12:1059–1071

    PubMed  CAS  Google Scholar 

  14. Anglicheau D, Pallet N, Rabant M, Marquet P, Cassinat B, Meria P, Beaune P, Legendre C, Thervet E (2006) Role of P-glycoprotein in cyclosporine cytotoxicity in the cyclosporine-sirolimus interaction. Kidney Int 70:1019–1025

    Article  PubMed  CAS  Google Scholar 

  15. Hotchkiss RS, Osmon SB, Chang KC, Wagner TH, Coopersmith CM, Karl IE (2005) Accelerated lymphocyte death in sepsis occurs by both the death receptor and mitochondrial pathways. J Immunol 174:5110–5118

    PubMed  CAS  Google Scholar 

  16. Barbari AG, Masri MA, Stephan AG, El Ghoul B, Rizk S, Mourad N, Kamel GS, Kilani HE, Karam AS (2006) Cyclosporine lymphocyte maximum level monitoring in de novo kidney transplant patients: a prospective study. Exp Clin Transplant 4:400–405

    PubMed  CAS  Google Scholar 

  17. Falck P, Asberg A, Guldseth H, Bremer S, Akhlaghi F, Reubsaet JL, Pfeffer P, Hartmann A, Midtvedt K (2008) Declining intracellular T-lymphocyte concentration of cyclosporine a precedes acute rejection in kidney transplant recipients. Transplantation 85:179–184

    Article  PubMed  CAS  Google Scholar 

  18. Mardigyan V, Giannetti N, Cecere R, Besner JG, Cantarovich M (2005) Best single time points to predict the area-under-the-curve in long-term heart transplant patients taking mycophenolate mofetil in combination with cyclosporine or tacrolimus. J Heart Lung Transplant 24:1614–1618

    Article  PubMed  Google Scholar 

  19. Farrell RJ, Menconi MJ, Keates AC, Kelly CP (2002) P-glycoprotein-170 inhibition significantly reduces cortisol and ciclosporin efflux from human intestinal epithelial cells and T lymphocytes. Aliment Pharmacol Ther 16:1021–1031

    Article  PubMed  CAS  Google Scholar 

  20. Laplante A, Demeule M, Murphy GF, Beliveau R (2002) Interaction of immunosuppressive agents rapamycin and its analogue SDZ-RAD with endothelial P-gp. Transplant Proc 34:3393–3395

    Article  PubMed  CAS  Google Scholar 

  21. Serkova N, Hausen B, Berry GJ, Jacobsen W, Benet LZ, Morris RE, Christians U (2000) Tissue distribution and clinical monitoring of the novel macrolide immunosuppressant SDZ-RAD and its metabolites in monkey lung transplant recipients: interaction with cyclosporine. J Pharmacol Exp Ther 294:323–332

    PubMed  CAS  Google Scholar 

  22. Rodrigues AC, Curi R, Britto LR, Rebbechi IM, Hirata MH, Bertolami MC, Bernik MM, Dorea EL, Hirata RD (2006) Down-regulation of ABCB1 transporter by atorvastatin in a human hepatoma cell line and in human peripheral blood mononuclear cells. Biochim Biophys Acta 1760:1866–1873

    PubMed  CAS  Google Scholar 

  23. Crettol S, Venetz JP, Fontana M, Aubert JD, Ansermot N, Fathi M, Pascual M, Eap CB (2008) Influence of ABCB1 genetic polymorphisms on cyclosporine intracellular concentration in transplant recipients. Pharmacogenet Genomics 18:307–315

    Article  PubMed  CAS  Google Scholar 

  24. Donnenberg VS, Burckart GJ, Zeevi A, Griffith BP, Iacono A, McCurry KR, Wilson JW, Donnenberg AD (2004) P-glycoprotein activity is decreased in CD4+ but not CD8+ lung allograft-infiltrating T cells during acute cellular rejection. Transplantation 77:1699–1706

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The authors wish to acknowledge Dr. P.Y. Wong, Toronto General Hospital, for his expert advice on cyclosporine measurements.

Author information

Authors and Affiliations

  1. Heart Failure and Transplant, Division of Cardiology, University Health Network, Toronto General Hospital, Toronto, ON, Canada

    Finn Gustafsson, Diego H. Delgado, Meerna Nsouli, Jill Sheedy & Heather J. Ross

  2. Department of Hematology, University Health Network, Toronto General Hospital, Toronto, ON, Canada

    David Barth

  3. Department of Cardiology, Rigshospitalet 2142, Copenhagen University Hospital, 9 Blegdamsvej, 2100, Copenhagen, Denmark

    Finn Gustafsson

Authors
  1. Finn Gustafsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David Barth
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Diego H. Delgado
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Meerna Nsouli
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jill Sheedy
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Heather J. Ross
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Finn Gustafsson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gustafsson, F., Barth, D., Delgado, D.H. et al. The impact of everolimus versus mycophenolate on blood and lymphocyte cyclosporine exposure in heart-transplant recipients. Eur J Clin Pharmacol 65, 659–665 (2009). https://doi.org/10.1007/s00228-009-0663-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-009-0663-2

Keywords

Search

Navigation