Bioanalytical and DMPK Core

项目摘要(见说明)：BioAnalytic和DMPK Core将在本应用范围内确定的下列发现和临床前开发项目(1，2)中提供高通量的体外筛选和LC/MS/MS生物分析支持：1)进行一级DMPK筛选；2)对mGlu5 NAM发现化合物进行啮齿动物PK评估和随后的生物分析，以及评估在狗和非人灵长类动物身上进行外部测试的化合物的PK特性；以及3)在抑郁症的啮齿动物模型中对来自mGIU5发现候选者的生物介质进行生物分析，并建立所述研究的PK/PD关系。该中心由拥有制药业经验的关键人员组成，特别是在药物代谢和药代动力学(PK)研究和开发方面的经验，它将协助PK研究的设计，协调来自临床前药理学、确凿PK研究和非关键毒性研究的生物介质样本的接收和存储，以及来自第一阶段临床研究的血浆和尿液样本。Core还将实施Tier 1 DMPK筛查，包括随后的体外生物分析。DMPK科学家将采用当代方法进行基于LC/MS/MS的生物分析，使用最先进的质谱学和液相色谱设备，并遵守适用于非GLP PK研究的法规指南。最后，丹尼尔斯博士和他的DMPK团队将使用行业标准软件对数据进行PK分析，该软件能够对非临床研究产生的时间浓度曲线进行建模。

PROJECT SUMMARY (See instructions): The Bioanalytical and DMPK Core will provide high throughput in vitro screening and LC/MS/MS bioanalytical support in the following discovery and preclinical development Projects (1, 2) identified within this application: 1) perform the Tier 1 DMPK screening of; 2) perform the rodent PK assessment and subsequent bioanalysis of mGlu5 NAM discovery compounds as well as assess the PK properties of compounds testing externally in dogs and nonhuman primates; and 3) perform the bioanalysis of biological media originating from the behavioral pharmacology assessment of mGIU5 discovery candidates in rodent models of depression, as well as establish PK/PD relationships of said studies. Built with key personnel possessing experience from the pharmaceutical industry, specifically from drug metabolism and pharmacokinetic (PK) research and development experience, the Core will aid in PK study design, coordinate the receipt and storage of biological media samples originating from preclinical pharmacology, definitive PK studies and nonpivotal toxicity studies, as well as plasma and urine samples originating from Phase 1 clinical studies. The Core will also implement the Tier 1 DMPK screen, including subsequent in vitro bioanalysis. The DMPK scientist will adopt a contemporary approach to LC/MS/MS based bioanalysis employing state-of-the-art mass spectrometry and liquid chromatography equipment and an adherence to regulatory guidances appropriate for the nonGLP PK studies. Finally, Dr. Daniels and his DMPK team will perform PK analysis of the data employing industry-standard software capable of modeling time concentration profiles generated from nonclinical studies.