Drug at the Right Place & Concentration: Optimizing Combination Vaginal Ring

药物在正确的地方

• 批准号: 9197617
• 负责人: Mark Mitchnick
• 金额: $ 10.27万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9197617
• 关键词: 2' -deoxyadenosine; AIDS prevention; Anti-Retroviral Agents; Aspirate substance; Biological Assay; Biopsy; Blood; Cells; Cervical; Clinical; Clinical Research; Clinical Trials; Deoxyadenosines; Development; Diphosphates; Drug Kinetics; Evaluation; Female; Formulation; Fumarates; Funding; Guidelines; Human; In Vitro; Irrigation; Kenya; Laboratories; Measurement; Measures; Metabolism; Methods; Oral; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phase; Polyurethanes; Porifera; Prodrugs; RNA-Directed DNA Polymerase; Research Personnel; Sampling; Science; Seminal fluid; Technology; Tenofovir; Testing; Tissue Sample; Tissues; Universities; Utah; Vagina; Vaginal Ring; Validation; Work; analog; analytical method; cervicovaginal; human tissue; nonhuman primate; particle; polyether urethane; pre-exposure prophylaxis; preclinical safety; preclinical study; product development; programs; rectal; reproductive tract; tissue culture; tissue/cell culture; tripolyphosphate; vaginal fluid

PROJECT SUMMARY (See instructions): ~~~~ The objectives of the Bioanalytical Core are to develop and apply validated analytical methods for determination of drug levels for preclinical studies proposed in Projects 1 and 2 and for a pre-Phase I clinical study proposed in Project 3. The Core will also prepare intravaginal rings (IVRs) under Good Manufacturing Practice (GMP) to deliver tenofovir disoproxil fumarate (TDF), a more potent prodrug of tenofovir (TFV) with an excellent preclinical safety profile for a pre-Phase I pharmacokinetic (PK) study. The Core has developed and optimized bioanalytical methods to detect TDF and related metabolites for in vitro studies and will expand this work and validate as per ICH guidelines methods for quantification of GS7340, an alternative potent prodrug of tenofovir (TFV), as well as for IQP-0528, a pyrimidinedione with reverse transcriptase and entry inhibitory activity and maraviroc (MVC). The Core will also validate methods to detect intracellular concentrations of 2'deoxyadenosine triphosphate (dATP), the natural substrate and competitive analogue of tenofovir diphosphate (TFV-DP). Dr. Craig Hendrix, co-investigator, who is a leader in the development and validation of assays to measure TFV and TFV-diphosphate (the active metabolite) in blood, peripheral blood mononuclear cells (PBMCs), cervicovaginal lavages (CVL) and cervicovaginal (CV) aspirates, rectal sponges, and vaginal and cervical biopsy tissue for clinical trials, will expand the clinically validated UPLC/MS/MS methods established in his laboratory and develop assays to quantify TDF in clinical samples. Once validated to ICH and FDA standards, these assays (along with established TFV and TFV-DP assays) will be applied to the analysis of samples obtained in a pre-Phase I PK study proposed in Years 4 and 5 in Project 3. This will include measurements of TDF and appropriate metabolites in CV aspirates, cervical and vaginal biopsies, rectal sponges, and blood. The Core will leverage the ongoing work at Particle Sciences in the development of the TDF polyurethane intravaginal ring, regulatory testing, and filing of an IND and will support the development of the product and provide clinical supplies for the pre-Phase I vaginal ring study.

项目摘要（参见说明）：~~~~ 生物分析核心的目标是开发和应用经过验证的分析方法来确定项目 1 和 2 中提出的临床前研究以及项目 3 中提出的 I 期前临床研究的药物水平。该核心还将根据良好生产规范 (GMP) 制备阴道环 (IVR)，以提供富马酸替诺福韦二吡呋酯 (TDF)，这是一种更有效的替诺福韦前药 (TFV) 在 I 期前药代动力学 (PK) 研究中具有出色的临床前安全性。核心已经开发和优化了生物分析方法来检测 TDF 和相关代谢物，用于体外研究，并将扩大这项工作并根据 ICH 指南验证 GS7340（替诺福韦 (TFV) 的替代有效前药）以及 IQP-0528（一种具有逆转录酶和进入抑制活性的嘧啶二酮）和马拉维罗的定量方法。 （MVC）。该核心还将验证检测 2' 脱氧腺苷三磷酸 (dATP) 细胞内浓度的方法，dATP 是替诺福韦二磷酸 (TFV-DP) 的天然底物和竞争性类似物。共同研究员 Craig Hendrix 博士是血液、外周血单核细胞 (PBMC)、宫颈阴道灌洗液 (CVL) 和宫颈阴道 (CV) 抽吸物、直肠海绵以及阴道和宫颈活检组织中 TFV 和 TFV-二磷酸（活性代谢物）检测方法开发和验证的领导者 对于临床试验，他将扩展其实验室建立的经临床验证的 UPLC/MS/MS 方法，并开发定量临床样品中 TDF 的测定方法。 一旦按照 ICH 和 FDA 标准进行验证，这些测定（以及已建立的 TFV 和 TFV-DP 测定）将应用于对项目 3 第 4 年和第 5 年提出的前期 I PK 研究中获得的样品进行分析。这将包括测量 CV 抽吸物、宫颈和阴道活检、直肠海绵和血液中的 TDF 和适当代谢物。该核心将利用粒子科学公司在 TDF 聚氨酯阴道环的开发、监管测试和 IND 备案方面正在进行的工作，并将支持该产品的开发并为 I 期阴道环研究提供临床用品。