色瑞替尼有关物质遗传毒性（Q） SAR评价及Ames试验研究

Study on (Q)SAR Evaluation and Ames Test of Mutagenicity of Impurities in Ceritinib

关键词:  色瑞替尼  遗传毒性杂质  致突变性  (定量)构效关系  Ames试验

Key words:  ceritinib  genotoxic impurity  mutagenicity  (quantitative) structure activity relationship  Ames test

摘要:

目的 对色瑞替尼合成工艺中具有警示结构的潜在有关物质进行遗传毒性（致突变性）评价研究，为色瑞替尼有关物质的分类分级控制提供指导和依据。方法 分别采用基于专家规则和统计学原理的2种互补的（定量）构效关系[（Q） SAR]评价系统（Derek和Sarah）对色瑞替尼有关物质的遗传毒性进行初步预测和分类；对（Q） SAR预测结果为阳性的有关物质，开展Ames试验进一步验证。结果 杂质6 （CAS：1032903-50-6）、杂质7 （CAS：1032903-62-0）和杂质13 （CAS：1032903-63-1）的Derek预测结果均为阳性，依据ICH M7指导原则的分类为第3类。在Ames试验中，在加代谢活化系统S9和不加S9的情况下，3个杂质（每皿22~1 800 μg）回复突变的菌落数小于溶剂对照组的2倍，由此判定Ames试验提示的致突变性为阴性。结论 杂质6 、杂质7 和杂质13 的致突变性均为阴性，可推翻基于结构的疑虑，依据ICH M7中的第5类即非突变性杂质进行控制。

Abstract:

OBJECTIVE To evaluate the genotoxicity(mutagenicity) of potential process impurities with warning structure in the synthetic process of ceritinib, so as to provide guidance and basis for the classification and control of related substances of ceritinib. METHODS Two complementary(quantitative) structure-activity relationships[(Q)SAR] evaluation systems(Derek and Sarah) based on expert knowledge rules and statistics were used to predict and classify the impurities in ceritinib. Ames test was then used to further verify the (Q)SAR positive impurities. RESULTS Derek prediction results for impurity 6(CAS:1032903-50-6), impurity 7(CAS:1032903-62-0) and impurity 13(CAS:1032903-63-1) were all positive, and were classified into Class 3 according to the ICH M7 guidelines. In Ames test, the number of revertant colonies of three impurity in the presence or absence of metabolic activation system S9 in the range of 22-1 800 μg per plate of test substance was less than 2 times of that in the solvent control group, and the test result was negative. CONCLUSION The bacterial mutation test results of impurity 6, impurity 7 and impurity 13 are all negative, which can overturn the doubts based on the structure, and these impurities can be controlled as Class 5 in ICH M7, which namely non mutagenic impurity.