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。

IF 5.7 2区 医学 Q1 TOXICOLOGY Critical Reviews in Toxicology Pub Date : 2024-10-01 Epub Date: 2024-08-02 DOI:10.1080/10408444.2024.2374281
Puck Roos, Caroline Anggasta, Aldert H Piersma, Peter J K van Meer, Peter T Theunissen
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引用次数: 0

摘要

进行胚胎发育(EFD)研究是为了确定药物对孕妇和胚胎发育的风险。根据 ICH S5(R3) 指南,这些研究通常在一种啮齿动物和一种非啮齿动物物种(通常是大鼠和兔子)中进行。不过,在两个物种中进行 EFD 研究对风险评估的附加值还有待商榷。本研究评估了大鼠和兔子的 EFD 研究,以分析第二个物种的附加值。研究人员从荷兰药品评估委员会的数据库中收集了 2004 年至 2022 年期间针对提交给欧洲药品管理局申请上市许可的人类药品进行的大鼠和兔子 EFD 研究信息,以及针对已知人类致畸剂进行的 EFD 研究信息。数据库中共包含 369 种化合物。在大鼠和兔子的 EFD 研究中,55.6% 的化合物具有相似的效应。44.6%的化合物出现了不一致。不一致性通常可以根据母体毒性或化合物的作用机制来解释。对于其他化合物,由于暴露限度较高或不太关注 EFD 毒性,不一致性被认为临床意义有限。有 6.2% 的不一致性无法解释,被认为具有临床相关性。此外,对于特定的治疗类别,大鼠和兔子之间的一致性可能会有所不同。总之,在许多情况下,在两个物种中进行 EFD 研究的附加值是有限的。这些数据有助于确定可免除(额外)EFD 研究的情况,或创建证据权重模型,以确定是否需要进行(额外)EFD 研究。
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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.

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来源期刊
CiteScore
9.50
自引率
1.70%
发文量
29
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.
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