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Knockout mouse models are predictive of malformations or embryo-fetal death in drug safety evaluations
Natasha R Catlin1, Christine Stethem1, Christopher J Bowman1
1Pfizer, Inc., Groton, CT, USA.
Abstract:
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 to 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.
Insights
Knockout (KO) mouse data accurately predict drug-induced developmental toxicity, specifically malformations or embryo-fetal lethality (MEFL). This supports using KO models in risk assessments for pharmaceutical developmental toxicity.
Area of Science:
- Pharmacology
- Developmental Biology
- Toxicology
Background:
- Traditional pharmaceutical developmental toxicity assessment relies on two-species ICH guideline studies.
- Weight of evidence approaches, incorporating pharmacologic mode of action and genetic data, are gaining support.
- Concerns exist regarding the predictive accuracy of knockout (KO) mouse data for pharmaceutical target modulation.
Purpose of the Study:
- To assess the relevance and predictivity of adverse developmental effects in KO mouse models for pharmaceutical target modulation.
- To compare embryo-fetal development (EFD) study results with available KO mouse data for FDA-approved drugs.
Main Methods:
- Compared EFD study outcomes for 86 FDA-approved drugs (2017-2019) with publicly available KO mouse data.
- Analyzed the predictivity of KO mouse models for malformations, embryo-fetal lethality, and other adverse outcomes.
Main Results:
- KO mouse models demonstrated high predictivity for malformations or embryo-fetal lethality (MEFL) in EFD studies.
- Predictivity was lower for negative outcomes (i.e., no observed adverse effects) in EFD studies.
- Data suggest KO mouse models are valuable for assessing developmental toxicity risk.
Conclusions:
- Embryo-fetal toxicity data from KO mouse models are highly predictive of specific adverse outcomes.
- These findings support the integration of KO mouse data into weight of evidence approaches for pharmaceutical developmental toxicity risk communication.
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