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

药物在正确的地方

• 批准号: 8988537
• 负责人: Mark Mitchnick
• 金额: $ 31.64万
• 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
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8988537
• 关键词: 2' -deoxyadenosine; AIDS prevention; Anti-Retroviral Agents; Aspirate substance; Biological Assay; Biopsy; Blood; Cervical; Clinical; Clinical Research; Clinical Trials; Deoxyadenosines; Development; Diphosphates; Drug Kinetics; Evaluation; Female; Formulation; Fumarates; Funding; Guidelines; Human; In Vitro; Instruction; 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; Vaginal Sponges; Validation; Work; analog; analytical method; cervicovaginal; human tissue; in vivo; nonhuman primate; particle; polyether urethane; preclinical safety; preclinical study; product development; programs; rectal; reproductive tract; 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.

项目总结（请参阅说明）：~ 生物分析核心的目的是开发和应用经验证的分析方法，用于测定项目1和2中拟定的临床前研究以及项目3中拟定的I期前临床研究的药物水平。核心还将根据良好生产规范（GMP）制备阴道环（IVRs），以提供富马酸替诺福韦酯（TDF），这是一种更有效的替诺福韦（TFV）前药，具有良好的临床前安全性，可用于I期药代动力学（PK）研究。核心已经开发和优化了生物分析方法，以检测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指南验证定量方法GS 7340，替诺福韦（TFV）的替代强效前药，以及IQP-0528，具有逆转录酶和进入抑制活性的嘧啶二酮和马拉韦罗（MVC）。核心还将验证检测2 '脱氧腺苷三磷酸（dATP），天然底物和替诺福韦二磷酸（TFV-DP）的竞争性类似物的细胞内浓度的方法。克雷格亨德里克斯博士，合作研究者，他是TFV和TFV-二磷酸测定方法开发和验证的领导者用于临床试验的血液、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的（活性代谢物），将扩展其实验室中建立的临床验证的UPLC/MS/MS方法，并开发用于定量临床样本中TDF的测定方法。 根据ICH和FDA标准进行验证后，这些试验（沿着已确立的TFV和TFV-DP试验）将用于分析项目3第4年和第5年拟定的I期前PK研究中获得的样本。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。核心将利用粒子科学公司在开发TDF聚氨酯阴道环、监管测试和IND备案方面正在进行的工作，并将支持产品的开发，并为I期阴道环研究前提供临床供应。