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使用基于体外多电极阵列的测定法并结合脑内分布模型来预测小分子的癫痫发作易感性。

Predicting seizure liability of small molecules using an in vitro multi-electrode array based assay coupled with modeling of brain disposition.

作者信息

Belair David G, Kohnken Rebecca, McCloud Rebecca L, Sandoval Stephanie, Green Jonathon, Buck Wayne R, Polakowski James S

机构信息

Quantitative and Translational ADME Sciences, AbbVie Inc., 1 N Waukegan Rd, North Chicago, IL 60064, USA.

Preclinical Safety, AbbVie Inc., 1 N Waukegan Rd, North Chicago, IL 60064, USA.

出版信息

Curr Res Toxicol. 2025 Apr 26;8:100236. doi: 10.1016/j.crtox.2025.100236. eCollection 2025.

Abstract

Unintended central nervous system (CNS) effects of small molecule drugs can lead to costly attrition during drug development. CNS liability can be assessed with biochemical assays, as part of routine nonclinical toxicology studies, or via a battery of rodent CNS tests. Alternative in vitro methods have been developed for assessing CNS liability of small molecule drugs though their use in drug development has lagged relative to other organ systems of interest including cardiac, hepatic, and gastrointestinal. In the present study, 13 commercially available small molecule drugs and 15 experimental AbbVie compounds were evaluated in an in vitro seizure assay consisting of human-induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons cultured on a multi-electrode array (MEA). Across all 28 compounds, the in vitro seizure assay exhibited 58% sensitivity and 78% specificity. A mathematical model of brain penetrance was used to predict brain exposures in cynomolgus monkey and improved the concordance of the in vitro seizure assay with in vivo seizure liability, highlighting that the in vitro assay together with CNS exposure prediction could serve as a useful tool for characterizing seizure liability of a small molecule drug candidate.

摘要

小分子药物意外的中枢神经系统(CNS)效应可导致药物研发过程中产生高昂的损耗。作为常规非临床毒理学研究的一部分,CNS风险可以通过生化检测来评估,也可以通过一系列啮齿动物CNS试验来评估。虽然相对于包括心脏、肝脏和胃肠道在内的其他感兴趣的器官系统,用于评估小分子药物CNS风险的替代体外方法的使用在药物研发中滞后,但已经开发出来了。在本研究中,在一种体外癫痫发作试验中对13种市售小分子药物和15种实验性艾伯维化合物进行了评估,该试验由在多电极阵列(MEA)上培养的人诱导多能干细胞(hiPSC)衍生的谷氨酸能神经元组成。在所有28种化合物中,体外癫痫发作试验的灵敏度为58%,特异性为78%。使用脑渗透性数学模型来预测食蟹猴的脑暴露,并提高了体外癫痫发作试验与体内癫痫发作风险的一致性,这突出表明体外试验与CNS暴露预测一起可作为表征小分子候选药物癫痫发作风险的有用工具。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/25a0/12123357/8d1d5ef1f12d/ga1.jpg

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