European Journal of Clinical Pharmacology

, Volume 65, Issue 7, pp 659–665

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

  • Finn Gustafsson
  • David Barth
  • Diego H. Delgado
  • Meerna Nsouli
  • Jill Sheedy
  • Heather J. Ross
Clinical Trial

DOI: 10.1007/s00228-009-0663-2

Cite this article as:
Gustafsson, F., Barth, D., Delgado, D.H. et al. Eur J Clin Pharmacol (2009) 65: 659. doi:10.1007/s00228-009-0663-2

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 (R2 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 (R2 = 0.98), there was poor correlation between whole-blood C2 and lymphocyte AUC0–12 in patients treated with everolimus (R2 = 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.

Keywords

Proliferation signal inhibitors Rejection Calcineurin inhibitors Renal failure 

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Finn Gustafsson
    • 1
    • 3
  • David Barth
    • 2
  • Diego H. Delgado
    • 1
  • Meerna Nsouli
    • 1
  • Jill Sheedy
    • 1
  • Heather J. Ross
    • 1
  1. 1.Heart Failure and Transplant, Division of Cardiology, University Health NetworkToronto General HospitalTorontoCanada
  2. 2.Department of Hematology, University Health NetworkToronto General HospitalTorontoCanada
  3. 3.Department of CardiologyRigshospitalet 2142, Copenhagen University HospitalCopenhagenDenmark