Microfabricated tool for integrated PK/PD studies of CNS drugs

 描述（由申请方提供）：本提案的具体目的是测试开发一种用于同时连续测量药物浓度和脑电生理记录的工具的可行性，以用于中枢神经系统（CNS）候选药物的临床前试验。拟议工具的好处有三个方面：1）改进的进行体内药代动力学（PK）研究的方法，其在空间和时间分辨率上比微透析有数量级的改进，2）在细胞水平监测生理变化以改善对药效学（PD）的理解的能力，以及3）这些能力在单一工具中的组合减少了评价候选药物所需的动物数量。拟定探针将检测鲁拉西酮（拉图达），并将拟定探针的测量结果与传统PK技术微透析、血浆抽取和脑脊液（CSF）抽取进行直接比较，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任何药物（MW~300 Da）。目前，微透析用于确定药物在脑中的PK，但其劳动密集型、容易出错、不适合大量候选药物，并且在每个数据点10-20分钟时具有低时间分辨率（Griffin等人，2009; Loryan等人，2014）。此外，所提出的工具可以监测神经元放电的变化，其目前用于研究市售药物的效果，并且已被建议为改善候选药物评估的有效方式（Tan等人，2010; Depoortere等人，2005年）的报告。所提出的工具结合了PK和PD研究，以改善科学信息并减少所需的动物和劳动力。我们将通过以下方式实现我们的特定目标：1）制造硅探针并使用适体进行功能化，2）选择针对精神病药物鲁拉西酮（拉图达）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）使用拟定传感器和传统PK方法进行体内研究。本I期可行性研究的成功将通过准确检测生理相关鲁拉西酮浓度和伴随的24小时神经放电记录（PK研究期间的典型情况，取决于药物半衰期）来确定。

 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).