Everolimus exposure in cardiac transplant recipients is influenced by concomitant calcineurin inhibitor.
In two separate pharmacokinetic studies, the drug interaction between immunosuppressive agents was examined in a total of 12 cardiac transplant recipients by conversion of the concomitant immunosuppressant. In six patients under continuous tacrolimus therapy, the concomitant drug azathioprine was converted to everolimus (PK-TAC study). No significant effect on tacrolimus pharmacokinetic parameters was observed. In the second study in which the patients were converted from cyclosporine to tacrolimus under continuous everolimus therapy (PK-EVL study), a significant decrease in everolimus predose concentration (from 4.2 to 2.3 microg/L), maximum concentration (from 9.1 to 5.9 microg/L), and area under the concentration time curve (mean values decreased from 64.2 to 33.7 microg*h/L) was found, indicating a lower everolimus exposure. A pharmacokinetic interaction between cyclosporine and everolimus has been described previously for healthy volunteers after single-dose application and presumably originates from a comparatively greater inhibition of hepatic CYP3A4 or P-glycoprotein efflux transporter with a low-dose cyclosporine regimen. Our results confirm this interaction under clinical conditions and suggest close drug monitoring when converting the calcineurin inhibitor under concomitant mammalian target of rapamycin-inhibitor therapy.
Brandhorst
Gunnar
G
Department of Clinical Chemistry, University Hospital Goettingen, Goettingen, Germany. gunnar.brandhorst@med.uni-goettingen.de
Tenderich
Gero
G
Zittermann
Armin
A
Oezpeker
Cenk
C
Koerfer
Reiner
R
Oellerich
Michael
M
Armstrong
Victor William
VW
D019540:Area Under Curve; D001379:Azathioprine / Q000494:pharmacology; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000494:pharmacology; D004336:Drug Antagonism; D000068338:Everolimus; D005260:Female; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D016559:Tacrolimus / Q000097:blood / Q000493:pharmacokinetics*
D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D000068338:Everolimus; D001379:Azathioprine; D020123:Sirolimus; D016559:Tacrolimus