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（由申请人提供）：该提案的具体目的是测试开发一种工具的可行性，该工具可同时连续测量大脑中的药物浓度和电生理学记录，以用于中枢神经系统（CNS）候选药物的临床前测试。该工具具有三重优点：1）改进了体内药代动力学（PK）研究的方法，与微透析相比，空间和时间分辨率提高了几个数量级；2）能够监测细胞水平的生理变化，以提高对药效学（PD）的理解；3）将这些功能组合在一个工具中，减少了评估药物所需的动物数量。 候选药物。所提出的探针将检测鲁拉西酮 (Latuda)，并且使用所提出的探针进行的测量将直接与微透析、血浆抽取和脑脊液 (CSF) 抽取等传统 PK 技术进行比较，以证明其在药物开发中的实用性。通过我们使用适体作为检测机制，该平台可扩展以监测大脑中的大多数药物（MW~300 Da）。目前，微透析用于确定大脑中药物的 PK，但它是劳动密集型的，容易出错，不适合大量候选药物，并且每个数据点 10-20 分钟的时间分辨率较低（Griffin 等，2009；Loryan 等，2014）。此外，所提出的工具可以监测神经元放电的变化，目前用于研究市售药物的效果，并被建议作为改进候选药物评估的有效方法（Tan et al., 2010; Depoortere et al., 2005）。拟议的工具结合了 PK 和 PD 研究，以改进科学信息并减少所需的动物和劳动力。我们将通过以下方式实现我们的具体目标：1) 制造硅探针并用适体进行功能化，2) 选择针对精神药物鲁拉西酮 (Latuda) 的适体，3) 开发用于使用点神经记录和化学传感的电子器件，然后 4) 使用所提出的传感器和传统 PK 方法进行体内研究。这一第一阶段可行性研究的成功将取决于对生理相关鲁拉西酮浓度的准确检测以及伴随的 24 小时神经放电记录（通常在 PK 研究期间，取决于药物半衰期）。