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Knockout mouse models are predictive of malformations or embryo-fetal death in drug safety evaluations
Natasha R Catlin1, Christine M 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 developmental toxicity in embryo-fetal development (EFD) studies for pharmaceutical compounds. This supports using KO mouse models in risk assessments for drug safety.
Area of Science:
- Pharmacology
- Toxicology
- Developmental Biology
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 evaluate 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 in EFD studies.
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., absence of MEFL) 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.
- KO mouse data can be integrated into weight-of-evidence approaches for communicating pharmaceutical developmental toxicity risk.
- This supports the utility of KO mouse models in drug safety evaluations.
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