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Everolimus Exposure in Cardiac Transplant Recipients is Influenced by Concomitant Calcineurin Inhibitor

Brandhorst, Gunnar MD*; Tenderich, Gero MD, PhD; Zittermann, Armin PhD; Oezpeker, Cenk MD; Koerfer, Reiner MD, PhD; Oellerich, Michael MD*; Armstrong, Victor William PhD*

doi: 10.1097/FTD.0b013e318161a335
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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 μg/L), maximum concentration (from 9.1 to 5.9 μg/L), and area under the concentration time curve (mean values decreased from 64.2 to 33.7 μg*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.

From the *Department of Clinical Chemistry, University Hospital Goettingen, Goettingen, Germany; and †Department of Cardio-Thoracic Surgery, Heart Center North Rhine-Westphalia, Ruhr University Bochum, Bad Oeynhausen, Germany.

Received for publication June 27, 2007; accepted October 15, 2007.

Gunnar Brandhorst and Gero Tenderich equally contributed to this work.

Reprints: Dr. Gunnar Brandhorst, MD, University Hospital Goettingen, Department of Clinical Chemistry, 37075 Goettingen, Germany (e-mail: gunnar.brandhorst@med.uni-goettingen.de).

© 2008 Lippincott Williams & Wilkins, Inc.