Traditionally, understanding potential developmental toxicity from pharmaceutical exposures has been based on the results of ICH guideline studies in two species. However, support is growing for the use of weight of evidence approaches when communicating the risk of developmental toxicity, where the intended pharmacologic mode of action affects fundamental pathways in developmental biology or phenotypic data from genetically modified animals may increasingly be included in the overall assessment. Since some concern surrounds the use of data from knockout (KO) mice to accurately predict the risk for pharmaceutical modulation of a target, a deeper understanding of the relevance and predictivity of adverse developmental effects in KO mice for pharmacological target modulation is needed. To this end, we compared the results of embryo-fetal development (EFD) studies for 86 drugs approved by the FDA from 2017-2019 that also had KO mouse data available in the public domain. These comparisons demonstrate that data from KO mouse models are overall highly predictive of malformations or embryo-fetal lethality (MEFL) from EFD studies, but less so of a negative outcome in EFD studies. This information supports the use of embryo-fetal toxicity data in KO models as part of weight of evidence approaches in the communication of developmental toxicity risk of pharmaceutical compounds.

传统上，了解药物暴露的潜在发育毒性是基于 ICH 指南对两个物种的研究结果。然而，在传达发育毒性风险时，越来越多的人支持使用证据权重方法，其中预期的药理学作用模式会影响发育生物学的基本途径，或者来自转基因动物的表型数据可能会越来越多地纳入总体评估中。由于人们对使用基因敲除 (KO) 小鼠的数据来准确预测靶点药物调节的风险存在一些担忧，因此需要更深入地了解 KO 小鼠中药物靶点调节的不良发育影响的相关性和预测性。为此，我们比较了 2017 年至 2019 年 FDA 批准的 86 种药物的胚胎-胎儿发育 (EFD) 研究结果，这些药物也有公共领域的 KO 小鼠数据。这些比较表明，KO 小鼠模型的数据总体上高度预测 EFD 研究中的畸形或胚胎-胎儿致死率 (MEFL)，但对 EFD 研究中的负面结果的预测性较差。该信息支持在 KO 模型中使用胚胎-胎儿毒性数据作为传达药物化合物发育毒性风险的证据权重方法的一部分。