Fabre Kristin, Berridge Brian, Proctor William R, Ralston Sherry, Will Yvonne, Baran Szczepan W, Yoder Gorm, Van Vleet Terry R
Translational Research Institute for Space Health, Baylor College of Medicine, Houston, TX, USA and MPS Center of Excellence, Drug Safety & Metabolism, IMED Biotech Unit, AstraZeneca, Waltham, MA, USA.
National Toxicology Program, The National Institute of Environmental Health Sciences, 530 Davis Dr., Keystone Building, Durham, North Carolina, USA.
Lab Chip. 2020 Mar 17;20(6):1049-1057. doi: 10.1039/c9lc01168d.
Safety related drug failures continue to be a challenge for pharmaceutical companies despite the numerous complex and lengthy in vitro assays and in vivo studies that make up the typical safety screening funnel. A lack of complete translation of animal data to humans can explain some of those shortcomings. Differences in sensitivity and drug disposition between animals and humans may also play a role. Many gaps exist for potential target tissues of drugs that cannot be adequately modeled in vitro. Microphysiological systems (MPS) may help to better model these target tissues and provide an opportunity to better assess some aspects of human safety prior to clinical studies. There is hope that these systems can supplement current preclinical drug safety and disposition evaluations, filling gaps and enhancing our ability to predict and understand human relevant toxicities. The International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) MPS Affiliate is a group of pharmaceutical industry scientists who seek to expedite appropriate characterization and incorporation of MPS to potentially improve drug safety assessment and provide safer and more effective medicines to patients. In keeping with this mission, the IQ MPS Affiliate scientists have prepared a series of organotypic manuscripts for several key drug safety and disposition target tissues (lung, liver, kidney, skin, gastrointestinal, cardiovascular, and blood brain barrier/central nervous system). The goal of these manuscripts is to provide key information related to likely initial contexts of use (CoU) and key characterization data needed for incorporation of MPS in pharmaceutical safety screening including a list of characteristic functions, cell types, toxicities, and test agents (representing major mechanisms of toxicity) that can be used by MPS developers. Additional manuscripts focusing on testing biologically based therapeutics and ADME considerations have been prepared as part of this effort. These manuscripts focus on general needs for assessing biologics and ADME endpoints and include similar information to the tissue specific manuscripts where appropriate. The current manuscript is an introduction to several general concepts related to pharmaceutical industry needs with regard to MPS application and other MPS concepts that apply across the organ specific manuscripts.
尽管构成典型安全筛选流程的体外试验和体内研究众多、复杂且耗时，但与安全性相关的药物研发失败问题依然是制药公司面临的一大挑战。动物数据无法完全转化为人体数据，这可以解释其中的一些不足。动物和人类在敏感性和药物处置方面的差异也可能起到一定作用。对于药物的潜在靶组织，存在许多在体外无法充分模拟的情况。微生理系统（MPS）或许有助于更好地模拟这些靶组织，并提供在临床研究之前更好地评估人体安全性某些方面的机会。人们希望这些系统能够补充当前临床前药物安全性和处置评估，填补空白并增强我们预测和理解人体相关毒性的能力。国际制药开发创新与质量联盟（IQ）MPS分会是一群制药行业科学家组成的团体，他们致力于加快对MPS的适当表征和整合，以潜在地改善药物安全性评估，并为患者提供更安全、更有效的药物。为了实现这一使命，IQ MPS分会的科学家针对几个关键的药物安全性和处置靶组织（肺、肝、肾、皮肤、胃肠道、心血管以及血脑屏障/中枢神经系统）编写了一系列器官型手稿。这些手稿的目的是提供与可能的初始使用背景（CoU）相关的关键信息，以及将MPS纳入药物安全性筛选所需的关键表征数据，包括一系列可被MPS开发者使用的特征性功能、细胞类型、毒性和测试剂（代表主要毒性机制）。作为这项工作的一部分，还编写了另外一些关注基于生物学的治疗药物测试和药物代谢动力学及药物处置动力学考虑因素的手稿。这些手稿侧重于评估生物制剂和药物代谢动力学及药物处置动力学终点的一般需求，并在适当情况下包含与组织特异性手稿类似的信息。当前这份手稿介绍了与制药行业在MPS应用方面的需求相关的几个一般概念，以及适用于各器官特异性手稿的其他MPS概念。
