尼替西农胶囊orfadin（nitisinone）批准用于治疗Ⅰ型遗传性酪氨
商品名
Orfadin
研发与上市厂商
瑞典Swedish Orphan公司研制开发，2002年4月首次在美国上市。
适应证
本品适用于罕见儿科1型遗传性酪氨酸血症 (HT-1) 的治疗。作为酪氨酸和苯丙氨酸饮食限制的辅助用药。
药理
本品是羟苯丙酮酸二氧酶的竞争性抑制剂，该酶在酪氨酸分解代谢途径中可上调延胡索酰乙酰乙酸酶(FAH)。通过抑制HT-1患者酪氨酸的正常代谢，本品可预防代谢中间体马来酰乙酰乙酸盐和延胡索酰乙酰乙酸盐的累积。在HT-1患者中，这些代谢中间体被转换成毒性代谢物琥珀酰丙酮和琥珀酰乙酰乙酸盐，造成肝、肾毒性。琥珀酰丙酮还可抑制卟啉合成途径，导致5-氨基酮戊酸盐积累。作为羟苯丙酮酸二氧酶抑制剂，推测受本品影响的生化学参数包括尿琥珀酰丙酮、血浆琥珀酰丙酮和胆色素原 (PBG) 合酶的活性。
大鼠口服本品生物利用度在90%以上，且分布于各器官中，特别是在肝脏和肾脏，在这2个脏器中放射活性保持至给药后7天。在大鼠体内，本品经生物转换后经尿液排泄。
在19～39岁 (中位数32岁) 的健康男性志愿者中进行了本品单一剂量的药动学研究。以胶囊或液体制剂形式给予本品1mg/kg，血药浓度达峰时间分别为：胶囊制剂3小时，液体制剂15分钟。以药时曲线下面积和最大血药浓度分析，胶囊和液体制剂是生物等效的。平均终末半衰期为54小时。
临床评价
生化学作用
在25个国家的87家医院进行了一项开放性研究，为期6年以上，有207例HT-1患者参与，患者年龄中位数为9个月 (刚出生至21.7岁)。大多数患者 (87%) 的血浆琥珀酰丙酮水平减低到参照水平 (可检测水平) 以下，正常化时间的中位数为3.9个月；180例患者的PBG合酶活性增加到参照水平 (可检测水平) 内，正常化时间的中位数为0.3个月，这些参数的变化与治疗前相比具统计学意义 (P<0.001)。
对总体存活率的影响
数据显示，2个月以下单用饮食限制方法治疗的HT-1患者，2和4年的存活率均为29%。而本研究中，2个月以下接受饮食限制和本品治疗的患者，2和4年的存活率均为88%；6个月以下单用饮食限制方法治疗的HT-1患者，2和4年存活率分别为74%和60%，而本研究中，6个月以下接受饮食限制和本品治疗的HT-1患者的相应存活率均为94%。
不良反应
在用本品治疗的207例HT-1患者中，最常见的不良反应涉及肝胆系统 (肝肿瘤8%，肝功能衰竭7%)、视觉系统 (结膜炎2%，角膜混浊2%，畏光2%，眼睑炎1%，眼痛1%，白内障1%)、血液和淋巴系统(血小板减少3%，粒细胞减少3%，鼻衄1%)、皮肤系统(瘙痒1%，剥落性皮炎1%，斑丘疹1%，脱发1%)。
其他低于1%的不良反应包括死亡、癫痫、脑肿瘤、头痛、运动过度、紫绀、腹痛、腹泻、胃肠炎、消化道出血、牙齿变色、肝酶水平升高、肝功能障碍、肝肿大、脱水、低血糖、口渴、感染、败血症、支气管炎、呼吸衰竭、病理性骨折、停经、神经质和嗜睡。
注意事项
未适当限制酪氨酸和苯丙氨酸的摄入可导致血浆酪氨酸水平升高。血浆酪氨酸水平必须保持低于500mmol/L，以避免对眼 (角膜溃疡、角膜混浊、角膜炎、结膜炎、眼痛和畏光)、皮肤 (足底和手掌痛性过度角化) 和神经系统 (不同程度的智力低下和发育迟缓)的毒性作用。对于大多数患者，眼部症状是暂时的，持续不超过1周。有6例患者发病延续16～672天。本品治疗期间需进行眼科检查，如有不良反应症状出现，需立即检查血浆酪氨酸浓度。如果血浆酪氨酸水平超过500mmol/L，须采取更为严格的饮食限制。本品的剂量需进行调整以降低血浆酪氨酸浓度。
在用本品和饮食限制治疗的患者中观察到发生一过性血小板减少(3%)、粒细胞减少 (3%) 或两者同时发生 (1.5%)，其中1例发生这2种不良反应的患者在本品剂量从2mg/kg减少至1mg/kg后症状改善，另1例血小板减少的患者停药2周，血小板计数在其后的3个月里继续下降，5个月后逐渐恢复正常，其余患者的血小板和粒细胞计数在未改变本品剂量的情况下均逐渐正常化。此外，未见因这2种不良反应而发生感染或出血。本品治疗期间建议常规监测血小板和粒细胞计数。另外，还应常规监测肝功能。
用量与用法
本品的用量需个体化。推荐的起始剂量为一日1mg/kg，分早、晚2次在就餐前至少1小时给药。
先天性代谢缺陷儿童需由专业营养师设计低蛋白饮食。对于幼童，可在服药前将胶囊打开，将内含物混合于少量水、配方饮料或苹果酱中。
本品治疗必须使卟啉代谢正常化。如果治疗1个月内生化参数 (尿琥珀酰丙酮) 未正常化，剂量可增加至一日1.5mg/kg。而血浆琥珀酰丙酮要在治疗后3个月才会恢复正常。在治疗开始时和急性发作时，必须更为密切地监测各生化参数。特别是对于婴儿，一旦肝功能改善，剂量可增大至一日2mg/kg，这一剂量被认为是所有患者的最大剂量。
Orfadin® (nitisinone) .Swedish Orphan Biovitrum has the worldwide rights to this product. 
What is Orfadin?
Orfadin is a hard white capsule for oral use. Treatment with Orfadin should be started and monitoredby doctors who are experienced in the treatment of hereditary tyrosinemia type 1 (HT-1) patients.Orfadin contains the active substance nitisinone.
What is Orfadin used for?
Orfadin is used to treat hereditary tyrosinemia type 1 (HT-1), a rare childhood disease. In this diseasethe body is unable to completely break down the amino acid tyrosine. Harmful substances will beformed and accumulate in the body, causing progressive liver failure and liver cancer in youngchildren. It is used with a diet that restricts the amino acids tyrosine and phenylalanine.
Because hereditary tyrosinemia type 1 is a rare disease Orfadin was designated an ‘orphan medicine’ (a medicine used in rare diseases) on 29 December 2000.
The medicine can only be obtained with a prescription.
How is Orfadin used?
Orfadin should be started as early as possible and the dose of Orfadin adjusted to the patient. The recommended starting dose is 1 mg/kg body weight/day divided in 2 doses administered orally. The capsules may be opened and their contents mixed in a small amount of water or formula diet just before swallowing. Orfadin is intended for long-term use.
How does Orfadin work?
Tyrosine is broken down in the body by a number of enzymes. Patients with HT-1 lack one of these enzymes, and the tyrosine in their body is not properly eliminated, but is transformed instead into harmful substances. Nitisinone, the active substance in Orfadin, blocks the breakdown of tyrosinebefore it can be transformed into harmful substances. However, tyrosine will remain in the body andtherefore a special diet (with low tyrosine and phenylalanine content) must be followed when takingOrfadin.
How has Orfadin been studied?
The largest study of Orfadin has been in 257 patients in 87 different hospitals in 25 countries, as part of a ‘compassionate use’ programme (this is a programme through which doctors can request a medicine for one of their patients before the medicine is fully authorised). The effect of Orfadin on survival was studied, and compared to historical records (report of patient survival with diet only as published in medical journals).
What benefit has Orfadin shown during the studies?
The main benefit is that Orfadin has been shown to greatly extend life. For example, a baby less than 2 months old with HT-1 would normally have only a 28% chance of surviving 5 years using diet alone. With additional Orfadin treatment, the survival rate increases to 82%. The sooner treatment is started, the better the rate of survival.
What is the risk associated with Orfadin?
The most common side effects of Orfadin are the result of high tyrosine levels caused by patients not eating the right foods as well as rare cases of a decrease in platelet and white blood cell counts. For the full description of the side effects reported with Orfadin, please see the package leaflet. Orfadin should not be used in people who may be hypersensitive (allergic) to nitisinone or any of the other ingredients.
Why has Orfadin been approved?
The Committee for Medicinal products for Human Use (CHMP) decided that Orfadin seems to be an effective treatment of HT-1, particularly if started early before the patient’s liver is too damaged, and it provides a better outcome for patients than that reported in literature with diet alone. The CHMP decided that Orfadin’s benefits are greater than its risks and recommended that Orfadin be given marketing authorisation.
What information is still awaited for Orfadin?
The company that makes Orfadin has established a post-marketing surveillance program to monitor the use and safety of the medicine in the treatment of HT-1.
Other information about Orfadin:
The European Commission granted a marketing authorisation valid throughout the European Union for Orfadin to Swedish Orphan International AB on 21 February 2005.