The impact of everolimus versus mycophenolate on blood and lymphocyte cyclosporine exposure in heart-transplant recipients.
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 AUC(0-12) 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 AUC(0-12) in patients treated with MMF (R(2) = 0.98), there was poor correlation between whole-blood C2 and lymphocyte AUC(0-12) in patients treated with everolimus (R(2) = 0.24).


CONCLUSIONS
Standard blood CsA levels accurately predict intralymphocytic exposure to CsA in patients concomitantly treated with MMF but not in patients treated with everolimus.
Gustafsson
Finn
F
Heart Failure and Transplant, Division of Cardiology, University Health Network, Toronto General Hospital, Toronto, ON, Canada. finng@dadlnet.dk
Barth
David
D
Delgado
Diego H
DH
Nsouli
Meerna
M
Sheedy
Jill
J
Ross
Heather J
HJ
D000368:Aged; D016572:Cyclosporine / Q000097:blood / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D000068338:Everolimus; D005260:Female; D016027:Heart Transplantation / Q000276:immunology* / Q000502:physiology; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000627:therapeutic use*; D008214:Lymphocytes / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D000068338:Everolimus; D009173:Mycophenolic Acid; D020123:Sirolimus