(定量)构效关系评估帕瑞昔布钠有关物质遗传毒性  

(Quantitative) structure-activity relationship to assess genotoxicity of parecoxib sodium-related substances

作　　者：胡钖 牛剑钊[1] 关皓月[1] HU Yang;NIU Jian-zhao;GUAN Hao-yue(National Institutes for Food and Drug Control,Beijing 102629,China)

机构地区：[1]中国食品药品检定研究院,北京102629

出　　处：《中国新药杂志》2024年第15期1586-1594,共9页Chinese Journal of New Drugs

摘　　要：目的:基于合成工艺梳理帕瑞昔布钠原料药生产过程中可能产生的有关物质,评估其致突变性和致癌性,确定杂质类别,为药物生产工艺的优化以及终产品的质量控制提供依据。方法:帕瑞昔布钠中51个有关物质的遗传毒性通过数据库及2种(定量)构效关系[(quantitative) structure-activity relationship,(Q)SAR]预测软件进行评估,根据风险评估结果对有关物质的遗传毒性进行分类,并根据ICH M7指导原则制定相应的可接受限度。结果:梳理出的51个有关物质中,综合评估结果为阳性有9个,需要按遗传毒性杂质控制;综合评估结果为阴性的有37个,按非遗传毒性杂质控制;还有5个预测结果模棱两可,不确定是否为遗传毒性物质。结论:为了保证药物质量与安全,经(Q)SAR评估为阳性的有关物质其最高限度不得超过18 ppm,同时提示应针对帕瑞昔布钠中具有警示结构的9个潜在遗传毒性杂质建立科学、合理的质量控制方法。Objective: Based on the synthesis process, the impurities that may be generated during the production process of parecoxib sodium active pharmaceutical ingredient were sorted out to evaluate the mutagenicity and carcinogenicity of the relevant substances and determined in the categories of relevant substances. This study provided a basis for the optimization of the drug production process and the quality control of the final product. Methods: The genotoxicity of 51 related substances in parecoxib sodium was evaluated by a database. According to the risk assessment results, the genotoxicity was classified and the corresponding acceptable limits were formulated on the basis of ICH M7 guidelines. Results: Among the 51 relevant substances sorted out, 9 were positive in the comprehensive assessment, which needed to be controlled according to genotoxic impurities;37 in the comprehensive assessment results were negative and regarded as non-genotoxic impurities;5 predictions were also ambiguous and uncertain whether they were genotoxic. Conclusion: In order to ensure the quality and safety of drugs, the maximum limit of relevant substances assessed as positive by(Quantitative) structure-activity relationship [(Q)SAR] should not exceed 18 ppm, and it is suggested that scientific and reasonable quality control methods should be established for nine potentially genotoxic impurities with warning structures in parecoxib sodium.

关 键 词：遗传毒性 有关物质 帕瑞昔布钠 (定量)构效关系 警示结构 

分 类 号：R917[医药卫生—药物分析学]