Pre-Phase I Evaluations

第一阶段前期评估

• 批准号: 8404840
• 负责人: Craig Walter Hendrix
• 金额: $ 57.56万
• 依托单位: IMQUEST BIOSCIENCES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-22 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8404840
• 关键词: Anti-Retroviral Agents; Antiviral Agents; Biological Assay; Biological Markers; Blood; Cervical; Characteristics; Clinical; Clinical Research; Colon; Data; Data Set; Decision Making; Development; Distal; Dose; Drug Formulations; Drug Kinetics; Evaluation; Failure; Funding; Future; Gel; Goals; Grant; HIV; HIV Infections; HIV-1; Home environment; Hour; Image; In Vitro; Instruction; Laboratories; Licensing; Liquid substance; Lubricants; Measurement; Measures; Metabolic Clearance Rate; Methods; Modification; Outcome; Participant; Pathway interactions; Penetration; Perception; Performance; Permeability; Pharmaceutical Preparations; Pharmacodynamics; Phase; Placebos; Prevention; Program Research Project Grants; Questionnaires; Radiolabeled; Research; Research Design; Safety; Sampling; Sensory; Series; Sigmoid colon; Tenofovir; Tissue Sample; Tissues; Toxic effect; Toxicology; Vagina; Validation; Work; absorption; analytical method; comparative; experience; healthy volunteer; improved; microbicide; novel; phase 1 study; primary outcome; programs; radiotracer; rectal; rectal microbicide; research clinical testing; sex; spatiotemporal; success; vaginal microbicide

PROJECT SUMMARY (See instructions): This Proposal is part of a Program project grant focusing on combination antiretroviral microbicides formulated in a gels optimized or vaginal use and for rectal use for the prevention of sexually-tranmitted HIV infection. This project includes a series of pre-Phase I studies that will assess the pharmacokinetic, pharmacodynamic (anti-HIV efficacy and toxicity), and acceptability characteristics of a combination microbicide simultaneously. Specific Aim 1. Methods Validation. Develop and validate assays for 0528 in blood, tissue, and luminal fluid, improve tenofovir intracellular assay sensitivity, verify compatibility of radiolabels with gel formulations, and cross-validate HIV explant methods with existing IP/CP funded labs for comparability. Specific Aim 2. Impact of Rectal Gel Volume on Distribution Comparative pre-Phase I Study. Compare colonic distribution and permeability with 3.5 mL v. 10 mL rectal placebo gel to inform final dose formulation for pre-Phase I clinical studies in Aim 3 & Aim 4. Specific Aim 3. Exploratory 0528 gel pre-Phase I PK/PD/Acceptability Study. Compare the spatiotemporal distribution (cervicovaginal, rectal, systemic), explant tissue anti-HIV effect, toxicological assessment, and acceptability of the 0528 candidate gel formulation for vaginal and rectal dosing in an exploratory pre-Phase I clinical study. Specific Aim 4. Exploratory combination 0528/tenofovir pre-Phase I PK/PD/Acceptability Study. Compare the spatiotemporal distribution (cervicovaginal, rectal, systemic), explant tissue anti-HIV effect, toxicological assessment, and acceptability of the 0528/tenofovir candidate gel formulation for vaginal and rectal dosing in an exploratory pre-Phase I clinical study.

项目摘要（参见说明）： 该提案是一项计划项目赠款的一部分，重点是配制在凝胶中的组合抗逆转录病毒杀菌剂，优化或阴道使用和直肠使用，以预防性传播艾滋病毒感染。该项目包括一系列第一阶段前研究，将同时评估组合杀菌剂的药代动力学、药效学（抗艾滋病毒功效和毒性）和可接受性特征。 具体目标 1. 方法验证。开发和验证血液、组织和管腔液中 0528 的检测方法，提高替诺福韦细胞内检测灵敏度，验证放射性标记与凝胶制剂的兼容性，并与现有 IP/CP 资助的实验室交叉验证 HIV 外植体方法以实现可比性。 具体目标 2. 直肠凝胶体积对分布比较 I 期前研究的影响。将结肠分布和渗透性与 3.5 mL 与 10 mL 直肠安慰剂凝胶进行比较，以了解目标 3 和目标 4 中 I 期前临床研究的最终剂量配方。 具体目标 3. 探索性 0528 凝胶 I 期前 PK/PD/可接受性研究。在一项探索性 I 期临床前研究中，比较 0528 候选凝胶制剂用于阴道和直肠给药的时空分布（宫颈阴道、直肠、全身）、外植体组织抗 HIV 效果、毒理学评估和可接受性。 具体目标 4. 探索性组合 0528/替诺福韦 I 期 PK/PD/可接受性研究。在一项探索性 I 期临床前研究中，比较 0528/替诺福韦候选凝胶制剂用于阴道和直肠给药的时空分布（宫颈阴道、直肠、全身）、外植体组织抗 HIV 效果、毒理学评估和可接受性。