Puck Roos, Caroline Anggasta, Aldert H Piersma, Peter J K van Meer, Peter T Theunissen
{"title":"大鼠和兔子胚胎胎儿发育研究与药物的评估:第二物种的附加值。","authors":"Puck Roos, Caroline Anggasta, Aldert H Piersma, Peter J K van Meer, Peter T Theunissen","doi":"10.1080/10408444.2024.2374281","DOIUrl":null,"url":null,"abstract":"<p><p>Embryofetal development (EFD) studies are performed to characterize risk of drugs in pregnant women and on embryofetal development. In line with the ICH S5(R3) guideline, these studies are generally conducted in one rodent and one non-rodent species, commonly rats and rabbits. However, the added value of conducting EFD studies in two species to risk assessment is debatable. In this study, rat and rabbit EFD studies were evaluated to analyze the added value of a second species. Information on rat and rabbit EFD studies conducted for human pharmaceuticals submitted for marketing authorization to the European Medicines Agency between 2004 and 2022 was collected from the database of the Dutch Medicines Evaluation Board, along with EFD studies conducted for known human teratogens. In total, 369 compounds were included in the database. For 55.6% of the compounds similar effects were observed in rat and rabbit EFD studies. Discordance was observed for 44.6% of compounds. Discordance could often be explained based on occurrence of maternal toxicity or the compound's mechanism of action. For other compounds, discordance was considered of limited clinical relevance due to high exposure margins or less concerning EFD toxicity. For 6.2%, discordance could not be explained and was considered clinically relevant. Furthermore, for specific therapeutic classes, concordance between rat and rabbit could vary. In conclusion, in many cases the added value of conducting EFD studies in two species is limited. These data could help identify scenarios in which (additional) EFD studies could be waived or create a weight-of-evidence model to determine the need for (additional) EFD studies.</p>","PeriodicalId":10869,"journal":{"name":"Critical Reviews in Toxicology","volume":" ","pages":"619-633"},"PeriodicalIF":5.7000,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Evaluation of rat and rabbit embryofetal development studies with pharmaceuticals: the added value of a second species.\",\"authors\":\"Puck Roos, Caroline Anggasta, Aldert H Piersma, Peter J K van Meer, Peter T Theunissen\",\"doi\":\"10.1080/10408444.2024.2374281\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Embryofetal development (EFD) studies are performed to characterize risk of drugs in pregnant women and on embryofetal development. In line with the ICH S5(R3) guideline, these studies are generally conducted in one rodent and one non-rodent species, commonly rats and rabbits. However, the added value of conducting EFD studies in two species to risk assessment is debatable. In this study, rat and rabbit EFD studies were evaluated to analyze the added value of a second species. Information on rat and rabbit EFD studies conducted for human pharmaceuticals submitted for marketing authorization to the European Medicines Agency between 2004 and 2022 was collected from the database of the Dutch Medicines Evaluation Board, along with EFD studies conducted for known human teratogens. In total, 369 compounds were included in the database. For 55.6% of the compounds similar effects were observed in rat and rabbit EFD studies. Discordance was observed for 44.6% of compounds. Discordance could often be explained based on occurrence of maternal toxicity or the compound's mechanism of action. For other compounds, discordance was considered of limited clinical relevance due to high exposure margins or less concerning EFD toxicity. For 6.2%, discordance could not be explained and was considered clinically relevant. Furthermore, for specific therapeutic classes, concordance between rat and rabbit could vary. In conclusion, in many cases the added value of conducting EFD studies in two species is limited. These data could help identify scenarios in which (additional) EFD studies could be waived or create a weight-of-evidence model to determine the need for (additional) EFD studies.</p>\",\"PeriodicalId\":10869,\"journal\":{\"name\":\"Critical Reviews in Toxicology\",\"volume\":\" \",\"pages\":\"619-633\"},\"PeriodicalIF\":5.7000,\"publicationDate\":\"2024-10-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Critical Reviews in Toxicology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1080/10408444.2024.2374281\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/8/2 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"TOXICOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Critical Reviews in Toxicology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/10408444.2024.2374281","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/8/2 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"TOXICOLOGY","Score":null,"Total":0}
Evaluation of rat and rabbit embryofetal development studies with pharmaceuticals: the added value of a second species.
Embryofetal development (EFD) studies are performed to characterize risk of drugs in pregnant women and on embryofetal development. In line with the ICH S5(R3) guideline, these studies are generally conducted in one rodent and one non-rodent species, commonly rats and rabbits. However, the added value of conducting EFD studies in two species to risk assessment is debatable. In this study, rat and rabbit EFD studies were evaluated to analyze the added value of a second species. Information on rat and rabbit EFD studies conducted for human pharmaceuticals submitted for marketing authorization to the European Medicines Agency between 2004 and 2022 was collected from the database of the Dutch Medicines Evaluation Board, along with EFD studies conducted for known human teratogens. In total, 369 compounds were included in the database. For 55.6% of the compounds similar effects were observed in rat and rabbit EFD studies. Discordance was observed for 44.6% of compounds. Discordance could often be explained based on occurrence of maternal toxicity or the compound's mechanism of action. For other compounds, discordance was considered of limited clinical relevance due to high exposure margins or less concerning EFD toxicity. For 6.2%, discordance could not be explained and was considered clinically relevant. Furthermore, for specific therapeutic classes, concordance between rat and rabbit could vary. In conclusion, in many cases the added value of conducting EFD studies in two species is limited. These data could help identify scenarios in which (additional) EFD studies could be waived or create a weight-of-evidence model to determine the need for (additional) EFD studies.
期刊介绍:
Critical Reviews in Toxicology provides up-to-date, objective analyses of topics related to the mechanisms of action, responses, and assessment of health risks due to toxicant exposure. The journal publishes critical, comprehensive reviews of research findings in toxicology and the application of toxicological information in assessing human health hazards and risks. Toxicants of concern include commodity and specialty chemicals such as formaldehyde, acrylonitrile, and pesticides; pharmaceutical agents of all types; consumer products such as macronutrients and food additives; environmental agents such as ambient ozone; and occupational exposures such as asbestos and benzene.