Impact of everolimus: update on immunosuppressive therapy strategies and patient outcomes after renal transplantation

Abstract

Everolimus is an immunosuppressive agent used for the prophylaxis of acute rejection after kidney transplantation. Everolimus inhibits the activity of the serine/threonine kinase mammalian target of rapamycin (mTOR), a key enzyme that controls cell growth and metabolism, producing cell cycle arrest from the G1 to S phase. As a consequence, everolimus has antiproliferative and antineoplastic effects. Everolimus is a drug with a narrow therapeutic index. The pharmacokinetics of everolimus indicates a need for twice-daily dosing. Intra-and interindividual variability and drug-drug interactions suggest the need for therapeutic drug monitoring to maximize the efficacy/toxicity ratio. The good correlation between exposure (area under the concentration-time curve) and trough concentration indicates that monitoring of everolimus trough concentrations is an adequate strategy after kidney transplantation. Everolimus is indicated for low-to moderate-risk de novo kidney transplant candidates. There are no conclusive studies thus far indicating that everolimus can be used in high-risk patients, such as sensitized patients, retransplants, and African Americans. In de novo kidney transplant recipients, the recommended initial dose of everolimus is 0.75 mg twice daily, adjusted to maintain blood trough concentrations of 3-8 ng/mL, in combination with progressive reduction in blood trough cyclosporine concentrations to 25-50 ng/mL. In combination with reduced trough blood tacrolimus concentrations of 4-7 ng/mL the recommended initial dose of everolimus is 1.5 mg twice daily, adjusted to maintain trough blood concentrations of 3-8 ng/mL. Everolimus can also be used as a conversion strategy, mainly to preserve renal function and to manage patients with malignancy. There is no definition of the ideal strategy for conversion, ie, abrupt or sequential, initial dose of everolimus, or target therapeutic trough blood concentrations. Intensive monitoring is recommended after conversion, especially for acute rejection and proteinuria. Because mTOR is ubiquitous and central to many intracellular processes, an array of adverse reactions may occur, including delayed tissue regeneration, proteinuria, dyslipidemia, diabetes, myelosuppression, infertility, ovarian cysts, and mouth ulcers. Because long-term benefits are the goal of any immunosuppressive strategy, further investigations aiming to understand, prevent, and manage everolimus-related adverse reactions are necessary to mitigate the risks and improve tolerability, allowing maximization of all the benefits of this drug.

Long-term outcome of everolimus treatment in transplant patients

“…37 In general, drug discontinuation is linked to the occurrence of adverse events. In early studies, eg, Study 251, the incidence of suspected drug-related adverse events was comparable in all three groups (75.6%, 78.4%, and 73.5%, respectively).…”

Cost-Effectiveness Analysis of Everolimus versus Mycophenolate in Kidney Transplant Recipients Receiving No Pharmacological Prophylaxis for Cytomegalovirus Infection: A Short-Term Pharmacoeconomic Evaluation (12 Months)

“…Therefore, an emerging new immunosuppressive strategy combining EVR and reduced exposure to TAC in de novo kidney transplant recipients has been investigated in a US randomized trial and an ongoing global trial (NCT01950819). Nevertheless, there are concerns regarding the de novo use of EVR, including surgical wound complications, incidence and duration of delayed graft function, graft dysfunction, and proteinuria [23,24]. Compared with MPS, EVR treatment was not associated with lower effectiveness or higher costs regarding these particular outcomes in this 12-month analysis.…”

Clinical Pharmacology and Therapeutic Drug Monitoring of Immunosuppressive Agents

“…The EVL Cmin is a good surrogate marker of EVL exposure (AUC), and correlates with pharmacological response and clinical outcomes. Therefore, prospective dose adjustments to obtain and maintain a therapeutic EVL Cmin have the potential to improve efficacy and reduce toxicity [122].…”