Microfabricated tool for integrated PK/PD studies of CNS drugs

用于中枢神经系统药物综合 PK/PD 研究的微加工工具

• 批准号: 9042433
• 负责人: Brian Glenn Jamieson
• 金额: $ 38.45万
• 依托单位: DIAGNOSTIC BIOCHIPS, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9042433
• 关键词: Animal Testing; Animals; Area; Base Pairing; Behavioral; Binding; Brain; Central Nervous System Agents; Cerebrospinal Fluid; Chemicals; Clinical; Clinical Trials; Collection; Custom; DNA Sequence; Data; Detection; Diagnostic; Drug Kinetics; Electronics; Electrophysiology (science); Evaluation; Failure; Feasibility Studies; Goals; Half-Life; Health; Health Care Costs; Hour; Institutes; Legal patent; Letters; Licensing; Measurement; Measures; Mental disorders; Methods; Microdialysis; Monitor; Mus; Neurons; Noise; Performance; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; Physiologic Monitoring; Plasma; Preclinical Testing; Process; Production; Rattus; Reaction Time; Running; Science; Signal Transduction; Silicon; Site; Techniques; Technology; Testing; Tissues; aptamer; biochip; bipolar patients; cost; depressive symptoms; drug candidate; drug development; drug discovery; drug efficacy; drug market; experience; gamma-Aminobutyric Acid; improved; in vivo; novel; novel strategies; pre-clinical; preclinical evaluation; relating to nervous system; research and development; response; sensor; success; temporal measurement; tool

 DESCRIPTION (provided by applicant): The specific aim of this proposal is to test the feasibility of developing a tool for the simultaneous and continuous measurement of pharmaceutical drug concentrations and electrophysiology recording in the brain for preclinical testing of central nervous system (CNS) drug candidates. The benefits of the proposed tool are three-fold: 1) improved method of performing in vivo pharmacokinetics (PK) studies with orders of magnitude improvements in spatial and temporal resolutions over microdialysis, 2) the ability to monitor physiological changes at the cellular level for improved understanding of pharmacodynamics (PD) and 3) the combination of these capabilities in a single tool reduces the number of animals needed for evaluation of a drug candidate. The proposed probe will detect lurasidone (Latuda) and measurements with the proposed probe will be directly compared with traditional PK techniques microdialysis, plasma draw, and cerebral spinal fluid (CSF) draw to demonstrate utility in drug development. Through our use of aptamers as a detecting mechanism, this platform is extensible to monitor most any drug (MW~300 Da) in the brain. Currently, microdialysis is used to determine PK of drugs in the brain, but it is labor-intensive, error-prone, unsuitable for a significant number of drug candidates, and has low temporal resolution at 10-20 minutes per data point (Griffin et al., 2009; Loryan et al., 2014). Additionally, the proposed tool can monitor changes in neuronal firing, which is currently used to study the effect of marketed drugs and has been suggested as an effective way to improve the evaluation of drug candidates (Tan et al., 2010; Depoortere et al., 2005). The proposed tool combines PK and PD studies for improved scientific information and a reduction in required animals and labor. We will accomplish our specific aim by: 1) Fabricating silicon probes and functionalize with aptamers, 2) Selecting an aptamer against psychiatric drug lurasidone (Latuda), 3) Developing electronics for point-of-use neural recording and chemical sensing, and then 4) Performing in vivo studies with both the proposed sensor and traditional PK methods. Success in this Phase I feasibility study will be determined by will be determined by the accurate detection of physiologically relevant lurasidone concentrations and concomitant neural firing recording for 24 hours (typical during of a PK study, depending on drug half-life).

 描述（由适用提供）：该提案的具体目的是测试开发一种工具的可行性，以简单而连续测量大脑中药物浓度和电生理记录，以用于中枢神经系统（CNS）药物的临床前测试。所提出的工具的好处是三个方面：1）改进了在体内药代动力学（PK）研究的改进方法，其空间和临时分辨率的数量级改善了微透析的空间和临时解决方案，2）能够监测对这些动物的理解（PD）的细胞水平的生理变化的能力（PD），以及这些工具的组合量，该工具的组合量的数量是一项兼容性的组合，该工具的组合量是一项兼容性。毒品候选人。所提出的探针将检测到Lurasidone（Latuda），并使用所提出的探针进行测量将直接与传统的PK技术微透析，等离子体抽签和脑脊髓液（CSF）进行比较，以证明药物发育中的效用。通过使用适体作为检测机制，该平台极为监测大脑中大多数药物（MW〜300 DA）。目前，微透析用于确定大脑中的药物PK，但它是实验室密集型，容易出错的，不适合大量候选药物，并且每个数据点10-20分钟的临时分辨率较低（Griffin等，2009; Loryan等人，Loryan等，2014）。此外，所提出的工具可以监测神经元放电的变化，目前用于研究销售药物的作用，并被认为是改善对药物候选者评估的有效方法（Tan等，2010； Depoortere等，2005）。提出的工具结合了PK和PD研究，以改善科学信息，并减少所需的动物和劳动。我们将通过以下方式实现我们的特定目标：1）制造硅问题并使用适体功能化，2）选择针对精神药物lurasidone（latuda）的适体，3）为使用的神经记录和化学感传感的电子设备开发电子设备，然后4）在Vivo研究中与拟议的传感器和传统PK方法一起进行Vivo研究。在这一阶段，I可行性研究将取决于将通过准确检测物理相关的lurasidone浓度和伴随的神经射击记录24小时来确定的（通常在PK研究中，取决于药物半衰期）。