The role of everolimus in liver transplantation

Abstract

During the last 5 decades, liver transplantation has witnessed rapid development in terms of both technical and pharmacologic advances. Since their discovery, calcineurin inhibitors (CNIs) have remained the standard of care for immunosuppression therapy in liver transplantation, improving both patient and graft survival. However, adverse events, particularly posttransplant nephrotoxicity, associated with long-term CNI use have necessitated the development of alternate treatment approaches. These include combination therapy with a CNI and the inosine monophosphate dehydrogenase inhibitor mycophenolic acid and use of mammalian target of rapamycin (mTOR) inhibitors. Everolimus, a 40-O-(2-hydroxyethyl) derivative of mTOR inhibitor sirolimus, has a distinct pharmacokinetic profile. Several studies have assessed the role of everolimus in liver transplant recipients in combination with CNI reduction or as a CNI withdrawal strategy. The efficacy of everolimus-based immunosuppressive therapy has been demonstrated in both de novo and maintenance liver transplant recipients. A pivotal study in 719 de novo liver transplant recipients formed the basis of the recent approval of everolimus in combination with steroids and reduced-dose tacrolimus in liver transplantation. In this study, everolimus introduced at 30 days posttransplantation in combination with reduced-dose tacrolimus (exposure reduced by 39%) showed comparable efficacy (composite efficacy failure rate of treated biopsy-proven acute rejection, graft loss, or death) and achieved superior renal function as early as month 1 and maintained it over 2 years versus standard exposure tacrolimus. This review provides an overview of the efficacy and safety of everolimus-based regimens in liver transplantation in the de novo and maintenance settings, as well as in special populations such as patients with hepatocellular carcinoma recurrence, hepatitis C virus-positive patients, and pediatric transplant recipients. We also provide an overview of ongoing studies and discuss potential expansion of the role for everolimus in these settings.

An overview of experimental and early investigational therapies for the treatment of polycystic kidney disease

“…in the treatment of some human neoplasms in selected cases (early stage NSCLC [16], advanced renal cell carcinoma [17], hormone receptor-positive and human epidermal growth factor receptor 2-negative advanced breast cancer [18], Kaposi's sarcoma in renal-transplant recipients [19]) and in the prevention of transplant rejection [20,21]. mTOR exists as a part of two distinct protein complexes, named mTOR complex 1 (mTORC1) and mTOR complex 2.…”

Cardiovascular risk after orthotopic liver transplantation, a review of the literature and preliminary results of a prospective study

“…Thus, sirolimus was not approved in liver transplantation, although recent studies using lower doses showed an improved safety profile[66,67]. Viceversa, everolimus provides a new therapeutic option for liver transplant recipients, when introduced early after liver transplantation[68] particularly with respect to posttransplant nephrotoxicity and other adverse events associated with long- term administration of CNIs.…”

Long term outcomes of Everolimus therapy in de novo liver transplantation: a systematic review and meta-analysis of randomized controlled trials

“…4,5, 6 The comparators for such evaluations are the mammalian target of Rapamycin (mTOR) inhibitors; sirolimus and everolimus (EVR).Everolimus gained approval for use in liver transplant patients following its introduction as an immunosuppressant in renal transplantation. 7 Use of EVR is approved in combination with reduced dose tacrolimus (RTAC) after 30 days of liver transplant. 7 Several studies have looked at the efficacy and safety of either EVR monotherapy or reduced CnI dose combination therapy (EVR+RTAC) compared to the standard CnI therapy post-liver transplantation.…”