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

药物在正确的地方

• 批准号: 8448516
• 负责人: Mark Mitchnick
• 金额: $ 31.84万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-18 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8448516
• 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 Formulations; Drug Kinetics; Evaluation; Female; Funding; Genital system; 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; Tenofovir disoproxil fumarate; 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; 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.

项目概述（见说明）：~~~~