—Kalydeco(ivacaftor)-囊性纤维化(CF)的靶向缺陷蛋白治疗突破 美国食品药品监督管理局批准Kalydeco(ivacaftor)为治疗囊性纤维化(CF)的一种罕见型年龄6岁和以上有囊性纤维化跨膜电导调节器(cystic fibrosis transmembrane conductance regulator，CFTR)基因特异性G551D突变的患者。 CF 是一种严重的遗传病影响肺和其它器官最终导致早死亡。是基因突变(缺陷)引起，编码一种蛋白被称为CFTR，调节机体内离子(例如氯化物)和水转运。氯化物和水转运缺陷导致粘稠粘液的形成积聚在肺，消化道和机体其它部分导致严重呼吸和消化问题，以及其它并发症例如感染和糖尿病。 CF，在美国影响约30,000人，是高加索人群中最常见致命性遗传病。约占CF 的4 %，或粗略地1,200 人，被认为有 G551D突变。 FDA长官Margaret A. Hamburg, M.D.说“Kalydeco是个体化医疗–靶向药物治疗有特异性遗传构成患者鼓舞人的一个最佳实例，”“独特和互利伙伴关系导致Kalydeco的批准，用作为公司和患者组如他们协作可实现药物发展的大模型。” FDA在优先审评程序下约3个月审评和批准Kalydeco，该程序被指定加快审评药物。优先审评程序对可能提供比可供治疗有显著治疗进展的药物使用6个月审评，替代标准10个月审评。 Kalydeco被药物的处方使用者费用目标日期2012年4月18日提前批准和被指定为孤儿(罕见)药物，鉴定疾病为在美国影响少于 200,000人。 在有G551D突变患者中，Kalydeco，一种药丸与含脂肪食物一天服用2次，帮助CFTR基因制造蛋白功能更佳和结果改善肺功能和CF的其它方面例如体重增量增加。 FDA的药物评价和研究中心主任Janet Woodcock, M.D.说：“Kalydeco是靶向缺陷性CFTR蛋白，是囊性纤维化根本原因，第一个可得到的治疗” “这对囊性纤维化社会是突破性治疗因为当前治疗只治疗这种遗传病的症状。” 两项48-周，安慰剂-对照临床研究涉及213例患者，一项是在年龄12岁和以上患者和另一项在患者年龄6岁至11岁，被用于在有G551D突变CF患者中评价Kalydeco的安全性和疗效。在两项研究中，用KALYDECO治疗导致肺功能显著和持续改善。 Kalydeco是只在有G551D突变CF患者中有疗效。在CFTR基因中有两个拷贝的F508突变的CF患者中无效，这是造成CF最常见突变。如患者突变状态不知道，应使用FDA批准的CF突变试验确定是否存在G551D突变。 Kalydeco最常见副作用包括上呼吸道感染，头痛，胃痛，皮疹，腹泻，和头晕。 批准日期：2012年1月31日；公司：Vertex Pharmaceuticals Incorporated KALYDECOTM (ivacaftor)片 美国初次批准：2012年 一般描述 KALYDECO 片中活性成分是ivacaftor有下面化学名：N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4oxoquinoline-3-carboxamide. 其分子式是C24H28N2O3和分子量392.49。结构式如下： Ivacaftor是一种白色淡白色粉实际上不溶于水(<0.05 μg/mL)。可得到KALYDECO为淡蓝色胶囊-形，薄膜衣片为口服给药含150 mg ivacaftor。每片含无活性成分胶体二氧化硅，交联羧甲基钠，羟丙基甲基纤维素醋酸琥珀，乳糖一水合物，硬脂酸镁，微晶纤维素，和十二烷基硫酸钠。片膜衣含巴西棕榈蜡，FD&C蓝#2，PEG 3350，聚乙烯醇，滑石粉，和二氧化钛。印墨水含氢氧化铵，氧化铁黑，丙二醇，和虫漆。 作用机制 Ivacaftor是CFTR蛋白的一种增效剂。CFTR蛋白是在许多器官内上皮细胞表面存在的一种氯离子通道。Ivacaftor有利于增加氯离子运输通过增强G551D-CFTR蛋白的通道开放概率(或门控选通[gating])。 在体外，ivacaftor增加CFTR-介导的穿越上皮电流[transepithelial current, IT)在表达G551D-CFTR蛋白啮齿类细胞中加入一种环腺苷酸(cAMP)激动剂EC50为100 ± 47 nM后；然而，在缺乏cAMP激动剂时ivacaftor不增加IT。在表达G551D-CFTR蛋白的人支气管上皮细胞中加入一种有EC50为236 nM的cAMP激动剂后Ivacaftor也增加IT。在单通道膜片钳实验中用来自啮齿动物表达G551D-CFTR蛋白膜片钳Ivacaftor增加G551D-CFTR蛋白开放概率与加入PKA和ATP相比为10-倍。 适应证和用途 KALYDECO被分类为一种囊性纤维化跨膜电导调节器(cystic fibrosis transmembrane conductance regulator，CFTR)增效剂。KALYDECO是适用于在年龄6岁和以上，CFTR基因有一种G551D突变患者的囊性纤维化(CF)的治疗。如果患者的基因型是未知，应使用FDA批准的CF突变试验检测G551D突变的存在。(1) 使用的限制： （1）对在CFTR基因中F508del突变纯合子CF患者无效。(1, 14) （2）尚未研究在其它人群CF患者中研究KALYDECO。(1, 14) 剂量和给药方法 （1）年龄6岁和以上成年和儿童患者：每12小时与含脂肪食物口服1片150 mg。(2, 12.3) （2）在有中度和严重肝受损患者中减低剂量。(8.6, 12.3) （3）当与中度或强CYP3A抑制剂药物共同给药时减低剂量。(7.1, 12.3) 剂型和规格 片：150 mg (3) 禁忌证 无已知的。 警告和注意事项 （1）转氨酶升高(ALT或AST)：开始KALYDECO前，治疗头一年期间每3个月，和其后每年应评估转氨酶(ALT和AST)。发生增加转氨酶水平患者应严密监视直至异常解决。在有ALT或AST大于正常上限(ULN)的5倍患者应中断给药。转氨酶升高解决后，考虑恢复KALYDECO给药的获益和风险。(5.1, 6) （2）与CYP3A诱导剂使用：与强CYP3A诱导剂同时使用(如，利福平[rifampin]，圣约翰草[St. John’s Wort]) 实质上减低ivacaftor的暴露可能减弱有效性。所以，不建议共同给药(5.2, 7.2, 12.3)。 不良反应 最常见对KALYDECO药物不良反应(在CFTR基因中发生 ≥8%有一种G551D 突变CF患者)是头痛，口咽痛，上呼吸道感染，鼻充血，腹痛，鼻咽炎，腹泻，皮疹，恶心，和头晕。6.1) 药物相互作用 CYP3A抑制剂：当与强CYP3A抑制剂共同给药时，减低KALYDECO剂量至150 mg一周2次(如，酮康唑[ketoconazole])。当与中度CYP3A抑制剂共同给药时(如，氟康唑[fluconazole])减低KALYDECO剂量至150 mg每天1次。避免食物含柚子汁或塞维利亚桔子。(7.1, 12.3) 如何供应/贮存和处置 KALYDECOTM (ivacaftor)是以淡绿色，膜包衣，胶囊形含150 mg ivacaftor片供应。每片一侧印有字符“V 150”和另一侧平坦，和被包装如下： 56-计数盒(含4个独立泡卡每卡14片) NDC 51167-200-01和60-计数瓶NDC 51167-200-02 贮存在20-25ºC (68-77ºF)；外出时允许15-30ºC (59-86ºF) [见美国药典控制室温]。 FDA Approves KALYDECO™ (ivacaftor), the First Medicine to Treat the Underlying Cause of Cystic Fibrosis - FDA approval received 3 months after submission of New Drug Application - - KALYDECO approved to treat people with CF who have a specific genetic mutation - - Vertex launches a comprehensive financial assistance and patient support program - Kalydeco Generic Name: ivacaftor (EYE va KAF tor) Brand Names: Kalydeco What is Kalydeco? Kalydeco (ivacaftor) is used to treat cystic fibrosis in adults and children who are at least 6 years old. Kalydeco is for use only in patients with a specific gene mutation related to cystic fibrosis. Before you take Kalydeco, you may need a medical test to make sure you have this gene mutation. Kalydeco may also be used for purposes not listed in this medication guide. Important information about Kalydeco You should not use Kalydeco if you are allergic to ivacaftor. Before you take Kalydeco, tell your doctor if you have liver or kidney disease. Kalydeco should be taken with a food that contains fat, such as butter, peanut butter, eggs, cheese pizza. Follow your doctor's instructions very carefully. Grapefruit, grapefruit juice, and Seville oranges may interact with Kalydeco and lead to unwanted effects. Discuss the use of grapefruit and orange products with your doctor. To be sure Kalydeco is not causing harmful effects, your liver function will need to be checked with frequent blood tests. Visit your doctor regularly. There are many other drugs that can interact with Kalydeco. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor. Keep a list of all your medicines and show it to any healthcare provider who treats you. Before taking Kalydeco You should not use Kalydeco if you are allergic to ivacaftor. To make sure you can safely use Kalydeco, tell your doctor if you have any of these other conditions: •liver disease; or •kidney disease. FDA pregnancy category B. Kalydeco is not expected to harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment. It is not known whether ivacaftor passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby. How should I take Kalydeco? Take Kalydeco exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label. Kalydeco is usually taken once every 12 hours with a food that contains fat, such as butter, peanut butter, eggs, cheese pizza. Follow your doctor's instructions. To be sure Kalydeco is not causing harmful effects, your liver function will need to be checked with frequent blood tests. Visit your doctor regularly. Store Kalydeco at room temperature away from moisture and heat. See also: Kalydeco dosage (in more detail) What happens if I miss a dose? Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose. What happens if I overdose? Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. Overdose symptoms may include severe forms of some of the side effects listed in this medication guide. What should I avoid while taking Kalydeco? Grapefruit, grapefruit juice, and Seville oranges may interact with Kalydeco and lead to unwanted effects. Discuss the use of grapefruit and orange products with your doctor. This medication may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert. Kalydeco side effects Get emergency medical help if you have any of these signs of an allergic reaction to Kalydeco: hives; difficult breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have a serious side effect such as: •severe stomach pain; •chest pain, wheezing, feeling short of breath; •nausea, upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes); or •low blood sugar (headache, hunger, weakness, sweating, confusion, irritability, dizziness, fast heart rate, or feeling jittery). Less serious Kalydeco side effects may include: •headache; •nausea, diarrhea, stomach pain; •dizziness; •acne or mild rash; •joint or muscle pain; or •cold symptoms such as stuffy nose, sneezing, sore throat. This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. See also: Kalydeco side effects (in more detail) What other drugs will affect Kalydeco? Tell your doctor about all other medicines you use, especially: •bosentan (Tracleer); •conivaptan (Vaprisol); •dexamethasone (Cortastat, Dexasone, Solurex, DexPak); •imatinib (Gleevec); •isoniazid (for treating tuberculosis); •midazolam (Versed); •nefazodone; •St. John's wort; •an antibiotic such as clarithromycin (Biaxin), erythromycin (E.E.S., EryPed, Ery-Tab, Erythrocin, Pediazole), rifabutin (Mycobutin), rifampin (Rifadin, Rifater, Rifamate), rifapentine (Priftin), or telithromycin (Ketek); •antifungal medication such as fluconazole (Diflucan), itraconazole (Sporanox), ketoconazole (Nizoral), miconazole (Oravig), posaconazole (Noxafil), or voriconazole (Vfend); •a barbiturate such as butabarbital (Butisol), secobarbital (Seconal), pentobarbital (Nembutal), or phenobarbital (Solfoton); •heart or blood pressure medication such as digoxin (Lanoxin, digitalis), nicardipine (Cardene), or quinidine (Quin-G); •the hepatitis C medications boceprevir (Victrelis) or telaprevir (Incivek); •HIV/AIDS medication such as atazanavir (Reyataz), delavirdine (Rescriptor), efavirenz (Sustiva, Atripla), etravirine (Intelence), fosamprenavir (Lexiva), indinavir (Crixivan), nelfinavir (Viracept), nevirapine (Viramune), ritonavir (Norvir, Kaletra), or saquinavir (Invirase); •medicines used to prevent organ transplant rejection, such as cyclosporine (Gengraf, Neoral, Sandimmune) or tacrolimus (Prograf). •medicines to treat narcolepsy, such as armodafinil (Nuvigil) or modafinil (Progivil); or •seizure edication such as carbamazepine (Carbatrol, Equetro, Tegretol), felbamate (Felbatol), oxcarbazepine (Trileptal), phenytoin (Dilantin), or primidone (Mysoline). There may be other drugs that can interact with Kalydeco. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.