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首页> 外文期刊>Regulatory Toxicology and Pharmacology: RTP >Is sunitinib a Narrow Therapeutic Index Drug? - A systematic review and in vitro toxicology-analysis of Sunitinib vs. Imatinib in cells from different tissues
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Is sunitinib a Narrow Therapeutic Index Drug? - A systematic review and in vitro toxicology-analysis of Sunitinib vs. Imatinib in cells from different tissues

机译：舒尼替尼是一种窄治疗指数药物吗？ -舒尼替尼与伊马替尼在不同组织细胞中的系统评价和体外毒理学分析

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Narrow Therapeutic Index Drugs (NTIDs) are characterized by a small range between therapeutic and toxicological effect. Missing international harmonized definition for NTIDs the EMA does not even have a definition of NTIDs in contrast to the U.S. FDA, Health Canada, and the Japanese NIEIS. Sunitinib, a tyrosine kinase inhibitor (TIC), indicated for the treatment of certain cancer types, will be running off patent soon. Falling into the category of NTID would have a major impact on regulatory requirements for generic applications. Our analyses of metadata revealed numerous arguments in favor of a NTID designation. We used in vitro experiments to also give initial experimental answers. Five cell types of different tissue origin were examined for determination of IC50-values in cell viability assays. For comparison, the first-in-class TKI Imatinib was used as reference non-NTID drug. In addition, apoptotic proteins were investigated with respect to their expression and phosphorylation status. These in vitro experiments showed systematically higher toxicity of Sunitinib compared to Imatinib and a different expression and phosphorylation pattern of apoptotic proteins. In vitro data can only give preliminary results and further experiments with clinical blood samples and tumor biopsies are needed to finally clarify NTID status of Sunitinib. (C) 2016 Elsevier Inc. All rights reserved.
机译：窄治疗指标药物（NTIDs）的特征是治疗效果和毒理学效果之间的距离很小。缺少国际统一的NTID定义EMA与美国FDA，加拿大卫生部和日本的NIEIS相比，甚至没有NTID的定义。舒尼替尼是一种酪氨酸激酶抑制剂（TIC），可用于治疗某些类型的癌症，不久将失去专利保护。属于NTID类别将对通用应用程序的法规要求产生重大影响。我们对元数据的分析显示了支持NTID名称的众多论点。我们使用了体外实验，也给出了初步的实验答案。检查了五种不同组织来源的细胞类型，以在细胞活力测定中确定IC50值。为了进行比较，将一流的TKI伊马替尼用作参考非NTID药物。此外，研究了凋亡蛋白的表达和磷酸化状态。这些体外实验显示，与伊马替尼相比，舒尼替尼的系统毒性更高，并且凋亡蛋白的表达和磷酸化方式不同。体外数据只能提供初步结果，需要进一步的临床血样和肿瘤活检进一步实验，以最终阐明舒尼替尼的NTID状况。 （C）2016 Elsevier Inc.保留所有权利。

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