Devine Patrick J, Ekert Jason, Kopec Anna K, Stresser David M, Ramsden Diane, Szilagyi John, Hewitt Philip, Hardwick Rhiannon N, Laing Steven, Van Vleet Terry R, Moalli Maria, Bajaj Piyush
Discovery Toxicology, Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, MA, USA.
UCB Pharma, Cambridge, MA, USA.
ALTEX. 2025 Jul 25. doi: 10.14573/altex.2407122.
Microphysiological systems (MPS) are envisioned to improve drug approval success rates. Yet, integration of MPS into drug development processes has been hampered in part by uncertainties in data translation. To speed adoption, development of animal cell-based MPS is advocated by the pharmaceutical industry. In our view, animal MPS availability would fill a key gap in the ability to examine in vitro to in vivo translatability. Since in vivo animal data will be available and guide decision making in regulatory activities for the foreseeable future, there is significant opportunity for translational assessments. In vivo animal study findings that are recapitulated using in vitro models generated from the corresponding animal species provide validation that those models possess the relevant and necessary attributes, e.g., species-specific pharmacodynamics, metabolism, transport, susceptibility to toxicity, etc. Results from the corresponding human models can then be interpreted with greater confidence for the relevant context of use (COU). Some drugs do not get to the clinic due to adverse findings in animals, so there is considerably more data to directly compare to animal in vitro models than human systems. Another benefit of animal MPS is that drug candidates exhibiting animal safety findings might be easier to derisk, for example if the finding was observed in animal but not the corresponding human in vitro model. This paper reviews considerations and recommendations for adopting animal MPS models in drug discovery and development and describes how their deployment is consistent with 3Rs principles.
微生理系统（MPS）有望提高药物审批成功率。然而，MPS融入药物研发过程在一定程度上受到数据转化不确定性的阻碍。为加快其应用，制药行业倡导开发基于动物细胞的MPS。我们认为，动物MPS的可用性将填补体外到体内可转化性研究能力方面的关键空白。鉴于在可预见的未来体内动物数据将可获得并指导监管活动中的决策制定，进行转化评估存在重大机遇。使用源自相应动物物种的体外模型再现的体内动物研究结果，证明这些模型具备相关且必要的属性，例如物种特异性药效学、代谢、转运、对毒性的易感性等。然后，对于相关的使用背景（COU），可以更有信心地解释相应人类模型的结果。一些药物由于在动物身上出现不良发现而未能进入临床，因此与人类系统相比，有更多数据可直接与动物体外模型进行比较。动物MPS的另一个好处是，表现出动物安全发现的候选药物可能更容易降低风险，例如，如果该发现在动物身上观察到，但在相应的人类体外模型中未观察到。本文综述了在药物发现和开发中采用动物MPS模型的考虑因素和建议，并描述了其部署如何符合3R原则。
