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评估与使用先进的体外系统的类相应物相关的药物相互作用风险

Rune Aa Nørgaard¹, Deepak K Bhatt², Erkka Järvinen²

¹Development ADME, Novo Nordisk A/S, Måløv, Denmark (R.A.N., D.K.B., C.G.-J., C.S.); Clinical Pharmacology, Pharmacy, and Environmental Medicine, Department of Public Health, University of Southern Denmark, Odense, Denmark (E.J., T.B.S.); Department of Clinical Pharmacology, Odense University Hospital, Odense, Denmark (T.B.S.); and Centre for Applied Pharmacokinetic Research, School of Health Sciences, The University of Manchester, Manchester, United Kingdom (A.G.) RNQR@novonordisk.com CXLS@novonordisk.com.

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概括

像HepatoPac这样的先进的体外系统显示出与治疗的药物相互作用 (DDI) 评估的前景,比药物开发的传统方法提供了更具临床相关性的数据.

科学领域:

药理学和毒理学药理学和毒理学
药物代谢和药物相互作用

背景情况:

对治疗性的药物相互作用 (DDI) 评估是一个不断发展的领域,其确立的指导方针有限.
目前用于小分子DDI的体外方法可能无法准确地转化为基于的治疗方法.
需要更多临床相关的体外工具来评估DDI.

研究的目的:

研究先进的人类肝细胞在体外系统 (HepatoPac,球体,肝芯片) 的实用性,以评估诱导的药物代谢酶和运输体的变化.
评估这些系统预测涉及治疗性的药物相互作用的潜力.

主要方法:

使用了HepatoPac,球体和肝脏在芯片上的系统与人类肝细胞.
评估了CYP1A2,CYP2B6,CYP3A4,SLCO1B1和ABCC2mRNA表达和活性的调节.
测试了一种治疗性 (NN1177),蛋白质和小分子 (奥贝提可酸,阿贝马西克利布,里法皮辛) 的作用.

主要成果:

NN1177在HepatoPac,球体或芯片上的肝脏中没有抑制CYP1A2,CYP2B6或CYP3A4,与三明治培养肝细胞形成鲜明对比.
在任何复杂系统中都没有观察到NN1177对SLCO1B1和ABCC2mRNA的影响.
在整个系统中观察到诱导大小的显著变化 (例如,CYP3A4 mRNA上的利芬素);HepatoPac显示了对DDI评估的高潜力.

结论:

先进的体外系统,特别是HepatoPac,显示出对治疗性的临床相关药物相互作用评估的潜力.
这些复杂的细胞模型可能与类药物开发的传统方法相比,提供了更好的可翻译性.
需要对球体和肝脏芯片系统进行进一步评估,以确认它们的实用性.

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