左羟丙哌嗪和羟苯磺酸钙中2个1类杂质的遗传毒性(Q)SAR评价及质控限度评估
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摘要
目的:对左羟丙哌嗪和羟苯磺酸钙的已知杂质进行遗传毒性评价,并对现行标准杂质限度的合理性进行评价。方法:按照ICH M7指导原则的要求,采用基于专家知识规则的Derek和基于统计学的Sarah两类(Q)SAR评价系统,对左羟丙哌嗪的3个杂质右羟丙哌嗪、苯基哌嗪、缩水甘油,羟苯磺酸钙及其杂质I(氢醌)进行评价和分类。对于确定为遗传毒性杂质的,根据药物临床用量计算杂质的暴露量,并按照遗传毒性杂质相关指导原则的要求,对其标准限度进行评估。结果:右羟丙哌嗪、苯基哌嗪预测结果为阴性,缩水甘油和氢醌预测结果为阳性,且分类为1类。缩水甘油的标准限度低于可接受安全剂量。氢醌的标准限度过高,存在安全隐患。结论:缩水甘油和氢醌为1类遗传毒性杂质,缩水甘油的标准限度合理,氢醌的标准限度应该进一步严格。
Objective:To assess the genotoxicity of impurities in levodropropizine and calcium dobesilate,and to evaluate the limits of these impurities.Methods:According to ICH M7 guidelines,two(Q)SAR prediction methodologies were applied(expert rule-based Derek and statistical-based Sarah)to assess and classify three impurities in levodropropizine(dextrodropropzine,1-phenylpiperazine and glycidol),calcium dobesilate and its impurity I(hydroquinone).If any impurity was characterized as genotoxic,the potential exposure was calculated based on the dosage.Then the limit of a genotoxic impurity was evaluated according to guidelines of genotoxic impurities.Results:(Q)SAR evaluation showed that dextrodropropzine and 1-phenylpiperazine were non-mutagenic while glycidol and hydroquinone were positive,both of which were classified as class 1.The limit of glycidol was less than the acceptable intake,while the limit of hydroquinone was too high to ensure the safety of the drug.Conclusion:Glycidol and hydroquinone were class 1 genotoxic impurities.The limit of glycidol in levodropropizine was appropriate.The limit of hydroquinone in calcium dobesilat should be reduced.
Objective:To assess the genotoxicity of impurities in levodropropizine and calcium dobesilate,and to evaluate the limits of these impurities.Methods:According to ICH M7 guidelines,two(Q)SAR prediction methodologies were applied(expert rule-based Derek and statistical-based Sarah)to assess and classify three impurities in levodropropizine(dextrodropropzine,1-phenylpiperazine and glycidol),calcium dobesilate and its impurity I(hydroquinone).If any impurity was characterized as genotoxic,the potential exposure was calculated based on the dosage.Then the limit of a genotoxic impurity was evaluated according to guidelines of genotoxic impurities.Results:(Q)SAR evaluation showed that dextrodropropzine and 1-phenylpiperazine were non-mutagenic while glycidol and hydroquinone were positive,both of which were classified as class 1.The limit of glycidol was less than the acceptable intake,while the limit of hydroquinone was too high to ensure the safety of the drug.Conclusion:Glycidol and hydroquinone were class 1 genotoxic impurities.The limit of glycidol in levodropropizine was appropriate.The limit of hydroquinone in calcium dobesilat should be reduced.
引文
[1]EMA.EUROPEAN MEDICINES AGENCY(EMA).Guideline on the Limits of Genotoxic Impurities[EB/OL].2006.[2017-05-18].http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002903.pdf
[2]EUROPEAN MEDICINES AGENCY(EMA).Question&Answers on the CHMP Guideline on the Limits of Genotoxic Impurities[EB/OL].2010.[2017-05-18].http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002907.pdf
[3]FDA.U.S.FOOD AND DRUG ADMINISTRATION(FDA).DRAFT guidance for industry.Genotoxic and carcinogenic impurities in drug substances and products:recommended approaches[EB/OL].2008.[Withdrawn].
[4]ICH.M7:assessment and control of DNA reactive(mutagenic)impurities in pharmaceuticals to limit potential carcinogenic risk[EB/OL].2014.[2017-05-18].http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Multidisciplinary/M7/M7_Step_4.pdf
[5]KROES R,KLEINERE J,RENWICK A.The threshold of toxicological concern concept in risk assessment[J].Toxicol Sci,2005,86(2):226
[6]ICH.ADDENDUM TO ICH M7:assessment and control of DNA reactive(mutagenic)impurities in pharmaceuticals to limit potential carcinogenic risk[EB/OL].2015.[2017-05-18].http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Multidisciplinary/M7/M7_Addendum_Step_2.pdf
[7]ASHBY J,TENNANT RW.Definitive relationships among chemical structure,carcinogenicity and mutagenicity for 301 chemicals tested by the U.S.NTP[J].Mutat Res,1991,257(3):229
[8]POWLEY MW.(Q)SAR assessments of potentially mutagenic impurities:a regulatory perspective on the utility of expert knowledge and data submission[J].Regul Toxicol Pharmacol,2015,71(2):295
[9]SUTTER A,AMBERG A,BOYET S.et al.Use of in silico systems and expert knowledge for structurebased assessment of potentially mutagenic impurities[J].Regul Toxicol Pharmacol,2013,67(1):39
[10]GREENE N,DOBO KL,KENYON MO,et al.A practical application of two in silico systems for identification of potentially mutagenic impurities[J].Regul Toxicol Pharmacol,2015,72(2):335
[11]IARC,Glycidol Some Industrial Chemicals.IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Humans,Vol 77[R],France,2000:469
[12]AASA J,VARE D,HITESH VM,et al.Quantification of the mutagenic potency and repair of glycidol-induced DNA lesions[J].Mutation Res,2016,805(7):38
[13]Mc GREGOR D.Hydroquinone:an evaluation of the human risks from its carcinogenic and mutagenic properties[J].Crit Rev Toxicol,2007,37(10):887
[14]ZANASI A,LANATA L,FONTANA G,et al.Levodropropizine for treating cough in adults and children:a meta-analysis of published studies[J].Multidiscip Resp Med,2015,10(1):19
[15]中国药典2015年版.二部[S].2015:158,1225 Ch P 2015.VolⅡ[S].2015:158,1225
[16]EP 8.0[S].2014:2610,1733
[17]RABEL E,BALLARINI S,LEHR L.A randomized,double-blind,placebo-controlled,clinical study on the efficacy and safety of calcium dobesilate in the treatment of chronic venous insufficiency[J].Phlebology,2016,31(4)264
[18]NIH Hydroquinone:Carcinogenic Potency Database[EB/OL].2007.[2017-09-8].https://toxnet.nlm.nih.gov/cpdb/chempages/HYDROQUINONE.html
[2]EUROPEAN MEDICINES AGENCY(EMA).Question&Answers on the CHMP Guideline on the Limits of Genotoxic Impurities[EB/OL].2010.[2017-05-18].http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002907.pdf
[3]FDA.U.S.FOOD AND DRUG ADMINISTRATION(FDA).DRAFT guidance for industry.Genotoxic and carcinogenic impurities in drug substances and products:recommended approaches[EB/OL].2008.[Withdrawn].
[4]ICH.M7:assessment and control of DNA reactive(mutagenic)impurities in pharmaceuticals to limit potential carcinogenic risk[EB/OL].2014.[2017-05-18].http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Multidisciplinary/M7/M7_Step_4.pdf
[5]KROES R,KLEINERE J,RENWICK A.The threshold of toxicological concern concept in risk assessment[J].Toxicol Sci,2005,86(2):226
[6]ICH.ADDENDUM TO ICH M7:assessment and control of DNA reactive(mutagenic)impurities in pharmaceuticals to limit potential carcinogenic risk[EB/OL].2015.[2017-05-18].http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Multidisciplinary/M7/M7_Addendum_Step_2.pdf
[7]ASHBY J,TENNANT RW.Definitive relationships among chemical structure,carcinogenicity and mutagenicity for 301 chemicals tested by the U.S.NTP[J].Mutat Res,1991,257(3):229
[8]POWLEY MW.(Q)SAR assessments of potentially mutagenic impurities:a regulatory perspective on the utility of expert knowledge and data submission[J].Regul Toxicol Pharmacol,2015,71(2):295
[9]SUTTER A,AMBERG A,BOYET S.et al.Use of in silico systems and expert knowledge for structurebased assessment of potentially mutagenic impurities[J].Regul Toxicol Pharmacol,2013,67(1):39
[10]GREENE N,DOBO KL,KENYON MO,et al.A practical application of two in silico systems for identification of potentially mutagenic impurities[J].Regul Toxicol Pharmacol,2015,72(2):335
[11]IARC,Glycidol Some Industrial Chemicals.IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Humans,Vol 77[R],France,2000:469
[12]AASA J,VARE D,HITESH VM,et al.Quantification of the mutagenic potency and repair of glycidol-induced DNA lesions[J].Mutation Res,2016,805(7):38
[13]Mc GREGOR D.Hydroquinone:an evaluation of the human risks from its carcinogenic and mutagenic properties[J].Crit Rev Toxicol,2007,37(10):887
[14]ZANASI A,LANATA L,FONTANA G,et al.Levodropropizine for treating cough in adults and children:a meta-analysis of published studies[J].Multidiscip Resp Med,2015,10(1):19
[15]中国药典2015年版.二部[S].2015:158,1225 Ch P 2015.VolⅡ[S].2015:158,1225
[16]EP 8.0[S].2014:2610,1733
[17]RABEL E,BALLARINI S,LEHR L.A randomized,double-blind,placebo-controlled,clinical study on the efficacy and safety of calcium dobesilate in the treatment of chronic venous insufficiency[J].Phlebology,2016,31(4)264
[18]NIH Hydroquinone:Carcinogenic Potency Database[EB/OL].2007.[2017-09-8].https://toxnet.nlm.nih.gov/cpdb/chempages/HYDROQUINONE.html