TY - JOUR

T1 - The impact of everolimus versus mycophenolate on blood and lymphocyte cyclosporine exposure in heart-transplant recipients

AU - Gustafsson, Finn

AU - Barth, David

AU - Delgado, Diego H

AU - Nsouli, Meerna

AU - Sheedy, Jill

AU - Ross, Heather J

N1 - Keywords: Aged; Cyclosporine; Dose-Response Relationship, Drug; Female; Heart Transplantation; Humans; Immunosuppressive Agents; Lymphocytes; Male; Middle Aged; Mycophenolic Acid; Sirolimus

PY - 2009

Y1 - 2009

N2 - 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). CONCLUSION: Standard blood CsA levels accurately predict intralymphocytic exposure to CsA in patients concomitantly treated with MMF but not in patients treated with everolimus.

AB - 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). CONCLUSION: Standard blood CsA levels accurately predict intralymphocytic exposure to CsA in patients concomitantly treated with MMF but not in patients treated with everolimus.

U2 - 10.1007/s00228-009-0663-2

DO - 10.1007/s00228-009-0663-2

M3 - Journal article

C2 - 19458944

VL - 65

SP - 659

EP - 665

JO - European Journal of Clinical Pharmacology

JF - European Journal of Clinical Pharmacology

SN - 0031-6970

IS - 7

ER -