Multi-functional scaling methodology for translational pharmacokinetic and pharmacodynamic applications using integrated microphysiological systems (MPS).
Multi-functional scaling methodology for translational pharmacokinetic and pharmacodynamic applications using integrated microphysiological systems (MPS).
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DOI：
10.1039/c6ib00243a
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发表时间：
2017-04-18
期刊：
影响因子：
--
通讯作者：
Cirit M
中科院分区：
文献类型：
--
作者：
Maass C;Stokes CL;Griffith LG;Cirit M
微生理系统（MPS）为转化研究的药代动力学、药效学和生物学机制研究提供相关的体外生理环境。设计多 MPS 平台对于研究多器官系统至关重要。典型的设计方法，包括直接缩放和异速缩放，单独缩放每个 MPS，并且基于相对大小而不是函数。本研究的目的是开发一种新的多功能扩展方法，用于针对特定应用的集成多 MPS 平台设计。我们开发了一种使用机械建模和目标规范的优化方法，该方法考虑了多种 MPS 功能（例如药物吸收和代谢），同时确定系统设计参数。这种方法为两个假设的多 MPS 平台的设计提供了依据，该平台由肠道和肝脏（多 MPS 平台 I）和肠道、肝脏和肾脏（多 MPS 平台 II）组成，以在体外重现体内药物暴露。这允许建立临床相关的药物暴露-反应关系，这是疗效和毒理学评估的先决条件。将多功能缩放产生的设计参数与基于直接和异速缩放的设计进行比较。八种药物的人血浆时间浓度曲线用于为设计提供信息，并计算另外五种药物的曲线以在独立组上测试设计的平台。多功能缩放产生的暴露时间与体内数据非常一致，而直接和异速缩放方法导致暴露持续时间短。多功能缩放允许多 MPS 平台从体内到体外的适当缩放，并且在研究的案例中提供比标准 MPS 缩放方法更好地模拟体内暴露的设计。
Microphysiological systems (MPS) provide relevant physiological environments in vitro for studies of pharmacokinetics, pharmacodynamics and biological mechanisms for translational research. Designing multi-MPS platforms is essential to study multi-organ systems. Typical design approaches, including direct and allometric scaling, scale each MPS individually and are based on relative sizes not function. This study’s aim was to develop a new multi-functional scaling approach for integrated multi-MPS platform design for specific applications. We developed an optimization approach using mechanistic modeling and specification of an objective that considered multiple MPS functions, e.g., drug absorption and metabolism, simultaneously to identify system design parameters. This approach informed the design of two hypothetical multi-MPS platforms consisting of gut and liver (multi-MPS platform I) and gut, liver and kidney (multi-MPS platform II) to recapitulate in vivo drug exposures in vitro. This allows establishment of clinically relevant drug exposure-response relationships, a prerequisite for efficacy and toxicology assessment. Design parameters resulting from multi-functional scaling were compared to designs based on direct and allometric scaling. Human plasma time-concentration profiles of eight drugs were used to inform the designs, and profiles of an additional five drugs were calculated to test the designed platforms on an independent set. Multi-functional scaling yielded exposure times in good agreement with in vivo data, while direct and allometric scaling approaches resulted in short exposure durations. Multi-functional scaling allows appropriate scaling from in vivo to in vitro of multi-MPS platforms, and in the cases studied provides designs that better mimic in vivo exposures than standard MPS scaling methods.
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在药物发现的边界，片上的器官。
DOI：
10.1038/nrd4539
发表时间：
2015-04
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Esch EW;Bahinski A;Huh D
通讯作者：
Huh D
DOI：
10.1016/j.vascn.2012.04.001
发表时间：
2012-05
影响因子：
1.9
作者：
Grosberg A;Nesmith AP;Goss JA;Brigham MD;McCain ML;Parker KK
通讯作者：
Parker KK
影响因子：
4.5
作者：
Benet, Leslie Z.;Broccatelli, Fabio;Oprea, Tudor I.
通讯作者：
Oprea, Tudor I.
DOI：
10.1007/bf03190588
发表时间：
2004-04-01
影响因子：
1.9
作者：
Caldwell, GW;Masucci, JA;Hageman, W
通讯作者：
Hageman, W
影响因子：
5.2
作者：
Dryden, Matthew S.
通讯作者：
Dryden, Matthew S.