舒尼替尼
伊马替尼
酪氨酸激酶抑制剂
药理学
药品
体外
毒性
治疗指标
酪氨酸激酶
甲磺酸伊马替尼
医学
体外毒理学
癌症研究
生物
癌症
内科学
受体
生物化学
髓系白血病
作者
Bodo Haas,Konstantin Weber‐Lassalle,Roland Frötschl,Niels Eckstein
标识
DOI:10.1016/j.yrtph.2016.02.010
摘要
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 NIHS. Sunitinib, a tyrosine kinase inhibitor (TKI), 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.
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