当前位置：药品说明书与价格首页 >> 抗肿瘤药 >> 新药推荐 >> 肝癌肝移植可使用依维莫司（ZORTRESS）作为免疫抑制治疗

肝癌肝移植可使用依维莫司（ZORTRESS）作为免疫抑制治疗

2010-08-07 11:59:41 作者：新特药房来源：中国新特药网天津分站浏览次数：189 文字大小：【大】【中】【小】

简介： 肝癌肿瘤的肝移植受者可使用依维莫司作为免疫抑制治疗依维莫司是一种具有抗肿瘤特性的新型免疫抑制剂，该药的副作用很少，但是在肝移植中使用受限。西班牙马德里的Gomez-Camarero J及其同事在一家医 ...

肝癌肿瘤的肝移植受者可使用依维莫司作为免疫抑制治疗

依维莫司是一种具有抗肿瘤特性的新型免疫抑制剂，该药的副作用很少，但是在肝移植中使用受限。西班牙马德里的Gomez-Camarero J及其同事在一家医疗中心内评估了依维莫司对肝移植后肿瘤存活率的影响及其安全性。10名移植后被诊断为肿瘤的肝移植受者接受平均为期12.7（5.5-27.5）个月的依维莫司治疗，平均存活期为21.3（7.5-40.5）个月。结果显示，依维莫司组在6、12和24个月时的存活率均显著高于既往记录人群中14名患有相似肿瘤但未接受依维莫司的肝移植受者（100%、90%、72% vs. 50%、29%、14%；HR=4.6，95%可信区间：1.3-16.4；P=0.008）。在依维莫司治疗期间，无一例患者发生排斥反应。3名患者的肾功能改善。此外，研究中很少观察到严重不良反应和感染。 Gomez-Camarero等总结认为，依维莫司可安全用于患有肿瘤的肝移植受者，并可改善短期存活率，但是目前还需要开展进一步的研究以确定长期益处及安全性。

依维莫司可安全用于肝移植病人

加拿大多伦多综合医院多器官移植项目主任Ｌｅｖｙ医师，在美国移植学会２００４年年会上报告称，他们最近完成的研究表明，免疫抑制剂依维莫司ｅｖｅｒｏｌｉｍｕｓ　预防肝移植病人的排斥反应安全有效。
这项随机对照双盲研究历时１２个月，另加２４个月的开放标签延长期。共纳入１１９例肝移植病人，随机接受依维莫司１ｍｇ、２ｍｇ或４ｍｇ每日１次，加环孢素和皮质激素；或服用安慰剂加环孢素和皮质激素。
结果显示，在１２个月的研究期间，依维莫司组的停药率５７％～６４％　显著高于安慰剂组４３％　，其中约半数的病人归因于不良反应事件。
在继续开放标签组的病人中，服用依维莫司１ｍｇ者１０例、２ｍｇ８例、４ｍｇ２例。其中服用１ｍｇ者的完全缓解率为９１％，２ｍｇ者为７２．７％，４ｍｇ者为３３．３％。
分析表明，应用依维莫司治疗者血小板减少、高胆固醇血症的发生率均高于安慰剂组，１ｍｇ、２ｍｇ和４ｍｇ组分别为７％、１０％和１０％，而安慰剂组仅为３％；在１２个月和３６个月时，依维莫司组肾功能不全的发生率为１０％～２１％，安慰剂组为７％。
然而，研究者发现，多数病人的血小板计数在正常范围，提示除４ｍｇ组外，其血小板减少倾向不具临床重要意义。
Ｌｅｖｙ医师进一步解释说，应用各种剂量的依维莫司均安全，但大剂量组不良反应事件发生率有增高倾向，肌酐清除率亦见剂量相关效应。

ZORTRESS

Indication(s):

Organ rejection prophylaxis in renal transplant patients with low-moderate immunologic risk, in combination with basiliximab induction and reduced doses of cyclosporine and corticosteroids.

Pharmacology:

Everolimus binds to the cytoplasmic protein, FK506 Binding Protein-12, forming a complex that binds to and inhibits the mammalian target of rapamycin (mTOR). This interaction inhibits p70 S6 ribosomal protein kinase activity, resulting in inhibition of ribosomal S6 protein phosphorylation, subsequent protein synthesis and cell proliferation. This action consequently inhibits antigenic and interleukin (IL-2 and IL-15) stimulated activation and proliferation of T and B lymphocytes.

Clinical Trials:

A 24-month, multinational, open-label, randomized trial, involving 833 de novo renal transplant patients 18–70 years of age, evaluated everolimus 1.5mg/day or everolimus 3mg/day plus reduced doses of cyclosporine and corticosteroids to 1.44g/day mycophenolic acid plus standard doses of cyclosporine and corticosteroids. At 12 months, everolimus 1.5mg/day was shown to be comparable to mycophenolic acid with respect to efficacy failure (25.3% and 24.2%, respectively), defined as treated biopsy-proven acute rejection, graft loss, death or loss to follow-up. Additionally, the calculated mean glomerular filtration rate (GFR) for everolimus 1.5mg/day and mycophenolic acid were comparable at month 12 (54.6mL/min and 52.3mL/min, respectively).

Two multicenter, double-blind (for first 12 months), randomized trials enrolling 1171 total de novo renal transplant patients compared fixed doses of everolimus 1.5mg/day and 3mg/day combined with standard doses of cyclosporine and corticosteroids to mycophenolate mofetil 2g/day and corticosteroids. The 12-month analysis of GFR demonstrated increased rates of renal impairment in both everolimus groups compared to the mycophenolate mofetil group in both trials. Therefore, cyclosporine doses should be reduced when used in combination with everolimus, and everolimus trough concentrations should be adjusted and maintained between 3 to 8ng/mL using therapeutic drug monitoring.

Legal Classification:

Adults:

Give as soon as possible after transplantation. Swallow whole. ≥18yrs: Initially 0.75mg every 12 hours (1.5mg/day) in combination with reduced dose cyclosporine. May adjust dose at 4–5 day intervals to achieve everolimus trough concentration target range: 3–8ng/mL. Moderate hepatic dysfunction: reduce daily dose by 1/2 the initial daily dose. Initiate oral prednisone as soon as oral medication is tolerated.

Children:

<18yrs: not recommended.

Contraindication(s):

Sirolimus allergy.

Precaution(s):

Increased risk of infections, lymphomas and other malignancies (eg, skin). Avoid sun, UV light. High immunologic risk or prophylaxis in other organs: not established. Severe hepatic impairment or hereditary disorders (eg, galactose intolerance, Lapp lactase deficiency, glucose-galactose malabsorption): not recommended. Diabetes. Obtain everolimus and cyclosporine (see literature) whole blood concentrations periodically; and trough concentrations during dose adjustments. Monitor CBCs, renal function, urine protein, lipids, blood glucose, and for pneumonitis and infections. Pregnancy (Cat.C); use effective method of contraception during and up to 8 weeks after therapy. Nursing mothers: not recommended.

Interaction(s):

Avoid live vaccines, standard doses of cyclosporine. Increased risk of angioedema with ACE-inhibitors. Potentiated by CYP3A4 and/or P-glycoprotein inhibitors; avoid strong inhibitors (eg, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, grapefruit juice, digoxin); monitor and adjust dose with moderate inhibitors (eg, erythromycin, fluconazole, nicardipine, diltiazem, nelfinavir, indinavir, amprenavir), or CYP3A4 and P-glycoprotein substrate (eg, verapamil). Antagonized by CYP3A4 inducers (eg, carbamazepine, phenobarbital, phenytoin, efavirenz, nevirapine, St. John’s Wort); avoid strong inducers (eg, rifampin, rifabutin). Avoid simvastatin, lovastatin; monitor if used with atorvastatin or pravastatin. Caution with other nephrotoxic drugs, CYP3A4 or CYP2D6 substrates with a narrow therapeutic index.

Adverse Reaction(s):

Peripheral edema, GI upset, constipation, hypertension, anemia, infections (eg, UTI), hyperlipidemia, angioedema, malignancies (eg, lymphomas, skin), proteinuria, nephrotoxicity, graft thrombosis, delayed wound healing/dehiscence, polyoma virus infections (eg, BK virus-associated nephropathy), non-infectious pneumonitis (reduce or interrupt dose and/or manage with corticosteroids), thrombotic microangiopathy, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, new-onset diabetes post-transplant, male infertility.