MTOR Inhibitors and their Role in Modern Concepts of Immunosuppression

Abstract

Schwarz et al. [1], from the Department of Hepatobiliary and Liver Transplantation Surgery, Hospital Saint Antoine, Paris, report in this issue on major thoracic and/or abdominal surgery performed nine times in six liver transplant recipients, without discontinuation of mammalian target of rapamycin (mTOR) for baseline immunosuppression. Sirolimus or everolimus were given in three patients each; trough levels were 8–10 ng/ml for sirolimus and 6–8 ng/ml for everolimus. In addition, five patients received mycophenolate mofetil, while one patient received cyclosporine. No major complications were observed and none that could be particularly attributed to mTOR inhibitors. The findings demonstrate that major surgery is very feasible in patients receiving antiproliferative immunosuppressive agents without mTOR cessation, and the rate of complications does not exceed that observed in major surgery. The presented findings are important, even though they are from a single center and only a small patient population, particularly since single-center reports and single-center studies using sirolimus fostered the current opinion that mTOR inhibitors increase surgical complications [2, 3]. In order to understand the background of this global rumor, a closer look into the facts might be helpful. Between 1999 and 2011, mTOR inhibitors were approved by the regulatory agencies [4–8] (US FDA, European Medicines Agency [EMA]: sirolimus for renal transplantation; 2003 EMA: everolimus for renal and heart transplantation; 2009 FDA: everolimus for renal transplantation; 2012 EMA, FDA: everolimus for liver transplantation) and have become part of the immunosuppressive armamentarium in solid organ transplantation. Since the mid-1990 s, everolimus has been developed in combination with reduced cyclosporine exposure in renal and heart transplantation, followed by the combination of reduced tacrolimus exposure in liver transplantation around 2005 [9–11]. Sirolimus was initially developed with standard-exposure cyclosporine in renal transplantation and finally achieved approval in 1999, given cyclosporine is eliminated after 2–4 months, based on the evidence of enhanced nephrotoxicity in this combination. Official recommendations for dosing of everolimus is based on large prospective trials and should be monitored by trough levels between 3 and 8 ng/ml in all organs, while sirolimus should be targeted at 4–11 ng/ml with cyclosporine and thereafter 16–24 ng/ml. In addition, sirolimus never achieved approval in liver transplantation due to a black box warning indicating an increased risk of hepatic artery thrombosis and was not studied in heart transplantation [4–8]. Both compounds are different drugs, with opposing effects on cellular metabolism in combination with either cyclosporine or tacrolimus [12–14], particularly related to nephrotoxicity, but with otherwise similar side effects (e.g. hypercholesterolemia, wound healing, and incisional hernias). A particular clinical strength of the mTOR inhibitors is their direct antiviral [15] potential (which clearly distinguishes them from the inosine-50-monophosphate dehydrogenase [IMPDH] inhibitor class of antiproliferative agents) and their anti-tumor potential [16]. Setting the stage for the actors, our next question should be how to combine these substances; standard protocols Commentary: Preliminary Report of Major Surgery in Liver Transplant Recipients Receiving mTOR Inhibitors without therapeutic discontinuation.