April 26, 2010 — The US Food and Drug Administration (FDA) has approved everolimus tablets (Zortress; Novartis Pharmaceuticals Corp) for use with low-dose cyclosporine, basiliximab, and corticosteroids to prevent organ rejection in adult kidney transplant patients at low to moderate immunologic risk.   Everolimus exerts its immunosuppressant effect by binding to the mammalian target of rapamycin (mTOR), thereby preventing the proliferation of antigen-activated T cells.   "For patients who require a kidney transplant, the limited availability of organs underscores the urgent need for effective medicines that can help protect the survival of the transplanted organ for the patient," said David Epstein, division head of Novartis Pharmaceuticals, in a company news release, noting that the new product is the fifth in their growing portfolio of medications designed to provide additional treatment options for kidney transplant patients.   FDA approval was based on data from the largest single phase 3 clinical study to be conducted in kidney transplant patients, showing that everolimus-based therapy prevented acute organ rejection while using a 60% lower dose of cyclosporine compared with the control regimen (mycophenolic acid, cyclosporine, and corticosteroids).   Calcineurin inhibitors, such as cyclosporine, are commonly used as part of immunosuppressive regimens and are linked to renal injury and an increased risk for infections and malignant tumors. In the study, use of a lower dose in the everolimus group was linked to a decreased incidence of calcineurin inhibitor-related adverse events.   "Transplant recipients require lifelong immunosuppression, so there is a critical need for treatment regimens that protect the transplanted kidney and also reduce the side effects and infections associated with calcineurin inhibitors," said Diane M. Cibrik, MD, associate professor of medicine and medical director of transplant clinical research trials at the University of Michigan, Ann Arbor, in the news release. "Based on its different mode of action, Zortress offers the ability to reduce calcineurin inhibitors and may help to address this unmet need."   In the study, 20% or more of everolimus-treated patients experienced peripheral edema, constipation, hypertension, nausea, anemia, urinary tract infection, and hyperlipidemia.   Also, the rate of peripheral edema, dyslipidemia, and hyperlipidemia was 5% higher in those receiving everolimus and low-dose cyclosporine compared with mycophenolic acid and full-dose cyclosporine.   As with other immunosuppressive therapies, everolimus is linked to a potential risk for serious infection and malignant tumors, such as lymphoma. An increased risk for kidney graft thrombosis has also been reported.   Because of these safety concerns, a risk evaluation and mitigation strategy has been implemented to educate patients and clinicians regarding the safe use and risks of everolimus. The program includes a medication guide, a communications plan, and a timetable for submission of assessments.   Everolimus (Certican; Novartis) is currently used for kidney and heart transplantation regimens in more than 70 countries outside the United States. A phase 3 heart transplant trial is under way to support filing for FDA approval, and an international phase 3 liver transplant study is ongoing.   Everolimus, 5- and 10-mg tablets (Afinitor; Novartis), previously were approved by the FDA for the treatment of advanced renal cell carcinoma refractory to sunitinib or sorafenib therapy. 近日，FDA批准由诺华制药公司生产的依维莫司（everolimus）片可与小剂量环孢素、巴利昔单抗以及皮质类固醇药物联合使用，用于预防伴有低度至中度免疫风险的成人肾移植患者的器官排异反应。该药通过与哺乳动物雷帕霉素靶点（mTOR）结合，抑制抗原激活T细胞增殖，从而达到免疫抑制效果。目前，依维莫司已在美国以外的70多个国家被批准用于肾和心脏移植的药物治疗。 依维莫司（everolimus）是西罗莫司的衍生物，口服哺乳动物雷帕霉素(mTOR)抑制剂，涉及血管生成的信号转导通路。是西罗莫司（sirolimus，又称雷帕霉素，即rapamycin）的衍生物，故依维莫司又称40-O-（2-羟乙基）-雷帕霉素，或40-O-（2-羟乙基）-西罗莫司。以往依维莫司临床上主要用来预防肾移植和心脏移植手术后的排斥反应。其作用机制主要包括免疫抑制作用、抗肿瘤作用、抗病毒作用、血管保护作用。但最近报道的III期临床研究结果中，依维莫司可以显著延长转移性肾癌患者的生存时间，而且毒副作用较轻微。研究者将索拉非尼或舒尼替尼治疗失败的晚期转移性肾细胞癌患者随机分为治疗组（272例，依维莫司10mg每天）和对照组（138例，安慰剂），结果发生转移事件191例（治疗组101例[37%]；对照组90例[65%]；相对危险度0.30;95%CI0.22-0.40;p〈0.0001），平均无进展生存时间治疗组4.0个月，对照组1.9个月。不良事件治疗组与对照组相比，口腔炎（40％比8％）、皮疹（25％比4％）和疲劳（20％比16％）。治疗组22例（8％）患肺炎，其中大约三分之一位重症肺炎