FDA批准吡非尼酮和尼达尼布用于治疗特发性肺纤维化

来源：FDA和Medscape网站发布日期：2014-10-16近日FDA同时批准了罗氏的吡非尼酮（Pirfenidone,商品名Esbriet）和勃林格殷格翰的尼达尼布（Nintedanib,商品名Ofev）用于治疗特发性肺纤维化（Idiopathic Pulmonary Fibrosis,IPF）。IPF系指原因不明的下呼吸道的弥漫性炎症性疾病,虽然发病率较低,但预后很差,在这两个药批准之前,除了肺移植外并没有疗效确实可靠的药物。     

治疗特发性肺纤维化新药尼达尼布的研究进展

目的:介绍尼达尼布在特发性肺纤维化(IPF)治疗中的研究进展,为其临床应用提供参考。方法:查阅近年来国内外相关文献,对尼达尼布应用于IPF的药理机制、临床研究、安全性评价等方面的资料进行归纳和总结。结果与结论:尼达尼布在IPF治疗中能够减缓肺纤维化的进展,延缓肺功能下降,降低轻/中度肺纤维化的急性加重发生率,提高患者的生存质量,且临床使用相对安全。     

波生坦在IPF研究中效果良好

瑞士生物制药公司Actelion已经宣布，从国际肺部疾病波生坦（bosehtan）应用（BUILD）研究中得到的数据强力支持进一步评估波生坦（商品名Tracleer）（Ⅰ）用于治疗特发性肺纤维化（IPF）。     

尼洛替尼 （nilotinib hydrochloride monohydrate）

尼洛替尼 （nilotinib hydrochloride monohydrate）是由诺华制药公司（Novartis harms．Inc）开发的一种口服酪氨酸激酶抑制剂，商品名Tasigna。该药为口服胶囊剂，于2007年10月获美国FDA批准上市，是用于治疗慢性粒细胞白血病（CML）的二线药物。     

吡非尼酮

<正>吡非尼酮(prfenidone)是由美国Inter Mune生物制药公司研发、罗氏制药生产的纤维化抑制剂,于2014年10月15日获FDA批准在美国上市[1],商品名为Esbriet。该药用于治疗特发性肺纤维化(IPF),已于2008年2月在欧盟各国允许上市。吡非尼酮的中文化学名称:5-甲基-1-苯基-2-(1H)-吡啶酮;英文化学名称:5-methyl-1-phenylpyridin-2(1H)-one;分子式:C12H11NO;分子量:185.22;CAS登记号:53179-13-8。     

泊马度胺(Pomalidomide)

泊马度胺(pomalidomide)是美国Celgene制药公司开发的新型免疫调节剂,商品名为Pomalyst。2013年2月8日,美国食品和药品监督管理局(FDA)批准该药用于治疗复发性及难治性多发性骨髓瘤。泊马度胺的中文化学名称:3-氨基-N-(2,6-二氧代-3-哌啶基)邻苯二甲酰亚胺;英文化学名称:3-amino-N-(2,     

大鼠重复ig给予N-［（3-烯丙基-2-羟基）苯亚甲基-2-（4-苄基-高哌嗪-1-基）乙酰肼富马酸盐的药动学研究

目的 采用高效液相色谱-串联质谱法（HPLC-MS/MS）测定SD大鼠血浆中N-［（3-烯丙基-2-羟基）苯亚甲基］-2-（4-苄基-高哌嗪-1-基）乙酰肼富马酸盐（SM-1）,并计算大鼠重复ig给药的药动学参数,评价SM-1的药动学特征。方法 将60只健康SPF级SD大鼠随机分为阴性对照组、溶媒对照组和SM-1低、中、高剂量组,每组16只动物（阴性对照组和溶媒对照组为6只动物）,雌雄各半。每天ig给药1次,各组分别给予水、溶媒或SM-1 50、100、200 mg·kg^-1,给药体积10 mL·kg^-1,连续给药4周,于首次给药和末次给药阶段进行药动学采血测定。采用经验证的HPLC-MS/MS法测定SD大鼠血浆中SM-1浓度。使用Phoenix WinNonlin 7.0软件进行血药浓度-时间数据分析与药动学参数计算。结果 SD大鼠ig给予SM-1后,在50～200 mg·kg^-1剂量,SD大鼠体内的平均峰浓度（C_max）及药时曲线下面积（AUC_0～t）随剂量的增加而增加,各剂量组动物平均C_max及AUC_0～t比值与剂量比相近。连续给药后,低、中、高剂量组均未出现明显的蓄积。雌性大鼠SM-1的暴露高于雄性大鼠。结论 连续给药28 d后,SM-1在大鼠体内未出现明显的蓄积,雌性大鼠SM-1的暴露高于雄性大鼠。     

Nintedanib in ovarian cancer

Introduction: Advanced ovarian cancer remains an unmet clinical need. Angiogenesis is considered a therapeutic target in ovarian cancer, with bevacizumab, a monoclonal antibody against VEGF, being the first drug to show a progression-free survival benefit. Nintedanib is an oral tyrosine kinase inhibitor targeting VEGF receptor 1–3, FGFR 1–3 and PDGFR α and β, which has entered phase III trial development in ovarian cancer.

Areas covered: This article reviews the preclinical and clinical efficacy of nintedanib in ovarian cancer, its pharmacokinetic and pharmacodynamics profile, safety issues, together with an overview of clinical trials carried out so far. A literature search was made in PubMed for nintedanib, ovarian cancer, angiogenesis, and on ClinicalTrials.gov site for clinical trials with nintedanib.

Expert opinion: An ongoing phase III trial investigating nintedanib combined with first-line chemotherapy in ovarian cancer has shown a statistically significant progression free survival benefit, although there were toxicity issues. The true clinical benefit of nintedanib in ovarian cancer including its optimal treatment setting and dosage still need to be addressed.     

尼达尼布在家兔体内的药动学研究

摘 要 目的： 建立家兔血浆尼达尼布检测的高效液相色谱方法,研究尼达尼布在家兔体内的药动学。方法: 采用ZORBAX SB-C₁₈色谱柱为分离柱,以乙腈-0.1%三氟乙酸-水（35∶20∶45）为流动相,流速为1.0 ml·min^-1,检测波长为286 nm,柱温为35℃;以卡马西平为内标,血浆在碱性条件下经乙酸乙酯萃取后检测。雄性家兔6只,按20 mg·kg^-1的剂量耳缘静脉注射给予尼达尼布;分别在给药前和给药后不同时间点耳缘静脉采集血液,分离血浆待测。用DAS 3.0计算药动学参数。结果: 尼达尼布浓度在0.05～10.00 μg·mL^-1范围内线性关系良好（r=0.999 8）;低中高三个浓度（0.10,2.50,7.50 μg·mL^-1）的日内精密度RSD分别为5.55％、4.53％和2.74％,日间精密度RSD分别为6.15％、5.45％和3.15％;相对回收率分别为（98.50±5.47）％、（100.25±4.54）％和（99.94±2.74）％。6只家兔血浆尼达尼布浓度经DAS 3.0计算,尼达尼布的主要药动学参数如下：C_max为（3.01±0.35） μg·mL^-1,t_1/2为（4.38±1.53）h,AUC_0-t为（11.67±1.71）μg·h·mL^-1。结论:该方法简便、快速、准确,适用于家兔血浆尼达尼布浓度的测定及其药动学研究。尼达尼布在家兔体内呈一级动力学消除。     

Nintedanib for the treatment of non-small-cell lung cancer

Introduction: In NSCLC, increased microvessel count, often used as a measure of angiogenesis, has been correlated with poor prognosis and associated with advanced disease and inferior outcomes. In the clinical development of antiangiogenic therapies, two approaches have been used; the first has been to inhibit ligand binding and receptor activation using targeted antibodies, whereas the second has been to inhibit receptor activation using tyrosine kinase inhibitors that target VEGF receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and/or fibroblast growth factor receptor (FGFR). Nintedanib is a triple angiokinase inhibitor that simultaneously acts on VEGFR, PDGFR and FGFR. It has shown significant antiangiogenic and antineoplastic activities in vitro, in preventing tumor growth and overcoming drug resistance.

Areas covered: Medline search was used with the following keywords: non-small-cell lung cancer and nintedanib or BIBF 1120, ASCO abstracts 2013 with nintedanib, and Phase I and Phase II abstracts lung cancer and nintedanib.

Expert opinion: Recent Phase III trials have shown promising efficacy results of nintedanib in NSCLC; however, many questions still need to be answered before it is put into routine use.     

Nintedanib for the treatment of idiopathic pulmonary fibrosis

Introduction: Idiopathic Pulmonary Fibrosis (IPF) is an interstitial lung disease characterized by the progressive loss of pulmonary function, ultimately leading to respiratory failure and death. Two novel compounds, nintedanib and pirfenidone, have shown efficacy in reducing the rate of decline of lung function in IPF patients. The multiple tyrosine kinase inhibitor nintedanib has extensively being studied as a potential angiogenesis inhibitor in clinical against various neoplastic disorders. Afterwards, this compound was successfully tested in IPF.

Areas covered: Herein, the authors review the working mechanisms of nintedanib, its pharmacological profile, and its efficacy and safety for patients with IPF.

Expert opinion: Nintedanib has shown to be safe and effective in patients with IPF, with a favorable long-term safety profile. There is a lack of comparative trials of pirfenidone and nintedanib, and the choice of treatment is left to the physicians’ judgement. Future directions of nintedanib use are represented by the treatment of progressive fibrosing interstitial lung disease other than IPF, IPF with advanced functional impairment, and lung fibrosis secondary to connective tissue diseases. A promising safety profile for the combinational use of nintedanib and pirfenidone in IPF has also recently emerged.     

尼达尼布有关物质测定方法的建立

摘 要 目的：建立尼达尼布的有关物质测定方法,并进行方法学验证。方法: 采用XBridge RP C₁₈色谱柱（250 mm×4.6 mm,3.5 μm）,以甲醇-0.1%三氟乙酸为流动相进行梯度洗脱,流速为1.0 ml·min^-1,检测波长为287 nm,柱温为35℃,进样量为10μl。结果: 主成分与各杂质峰分离度良好,杂质1~4分别在0.103 0~1.030 4 μg·ml^-1（r=0.999 5）,0.202 9~1.014 5μg·ml^-1（r=0.999 7）, 0.199 9~0.999 6 μg·ml^-1（r=0.999 9）,0.200 6~1.002 9 μg·ml^-1（r=0.998 4）范围内线性关系良好,检测限分别为0.31,0.6,0.60,0.60 ng;平均回收率分别为98.3%、99.3%、97.9%、99.8%,RSD分别为2.1%、2.1%、3.0%、1.1%。结论:该方法简便,准确,灵敏度高,专属性强,适用于本品有关物质的测定。     

Nintedanib for the treatment of patients with advanced non-small-cell lung cancer

An unmet need remains for effective, well-tolerated treatment options in advanced non-small-cell lung cancer that can alleviate the disease burden for a broad selection of patients. Nintedanib (Vargatef) is a potent, oral, triple angiokinase inhibitor of three distinct pro-angiogenic pathways. A recent Phase III trial of second-line nintedanib plus docetaxel met the primary end point of progression-free survival and demonstrated significant benefit in the key secondary end point of overall survival, with median overall survival greater than 1 year for patients with adenocarcinoma histology. This article summarizes preclinical and clinical experience with nintedanib in non-small-cell lung cancer to date and discusses how it may be used in the future, including prospects for individualizing treatment by tumor proliferation dynamics and molecular biomarkers of response.     

Nintedanib:抗癌、抗肺纤维化的三联血管激酶抑制剂

血管生成被认为是癌症治疗的潜在靶向机制,血管内皮生长因子(VEGF)、血小板源生长因子(PDGF)、纤维母细胞生长因子(FGF)均为与血管生成相关的多能生长因子.勃林格殷格翰公司开发的新药nintedanib,2014年10月被FDA批准上市.其作为一种作用于VEGFR、PDGFR、FGFR的小分子三联血管激酶抑制剂,用于治疗特发性肺纤维化(IPF),肝衰竭和癌症,包括转移性非小细胞肺癌(NSCLC)、卵巢癌、前列腺癌和结肠癌、肾细胞癌等,在临床前研究中表现出独特药理作用,在一系列临床研究中显示出良好的治疗前景,且安全性及耐受性均较好.     

基于openFDA对吡非尼酮和尼达尼布药品不良反应的比较分析

目的：通过对特发性肺纤维化（IPF）治疗药物吡非尼酮与尼达尼布不良反应进行对比分析,为临床安全用药提供参考。方法：利用美国食品药品监督管理局公共数据项目（the US Food and Drug Administration Pubic Data Open Project,openFDA）中的不良反应端点的交互式图表板块访问不良反应应用程序接口（API）,检索2004年1月至2021年12月期间吡非尼酮与尼达尼布的不良反应报告,并对数据进行分析。结果与结论：吡非尼酮与尼达尼布的不良反应报告数分别为27753和13621份,男性总体不良反应事件多于女性,两种药物主要适应症为IPF,常见的不良反应为胃肠道反应、疲劳、呼吸困难和体重下降等,其中吡非尼酮以恶心最为常见,尼达尼布以腹泻居多。除皮肤相关的不良事件,吡非尼酮多数常见不良反应发生率和严重不良反应事件发生率均低于尼达尼布,其安全性相对更高。