Microfabricated tool for integrated PK/PD studies of CNS drugs

 描述(申请人提供)：这项建议的具体目的是测试开发一种工具的可行性，该工具用于同时和连续测量药物浓度和脑内电生理记录，用于中枢神经系统(CNS)候选药物的临床前测试。建议中的工具的好处有三个方面：1)改进了进行体内药代动力学(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)能够在细胞水平上监测生理变化，以改进对药效学(PD)的了解；3)在一个工具中结合这些功能，减少了评估候选药物所需的动物数量。建议的探测器将检测Lurasidone(Latuda)，使用建议的探测器的测量将直接与传统的PK技术微透析、血浆提取和脑脊液(CSF)提取进行比较，以证明在药物开发中的实用性。通过我们使用适配子作为检测机制，这个平台可以扩展到监测大脑中几乎任何药物(MW~300Da)。目前，微透析被用于确定大脑中药物的PK，但它劳动密集型、容易出错、不适合相当数量的候选药物，并且每个数据点10-20分钟的时间分辨率较低(Griffin等人，2009；Loryan等人，2014)。此外，拟议的工具可以监测神经元放电的变化，神经元放电目前被用于研究上市药物的效果，并已被建议为改善对候选药物的评估的有效方法(Tan等人，2010年；Depoortere等人，2005年)。建议的工具结合了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)制作硅探针并与适配子一起功能化；2)选择针对精神药物卢拉西酮(Latuda)的适配子；3)开发用于使用点神经记录和化学传感的电子器件；4)用所提出的传感器和传统的PK方法进行体内研究。这项第一阶段可行性研究的成功与否将取决于准确检测与生理相关的卢拉西酮浓度以及伴随的24小时神经放电记录(通常在PK研究期间，取决于药物的半衰期)。

 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).