Pre-Phase I Evaluations

项目总结（见说明）： 该提案是一项计划项目赠款的一部分，重点是以凝胶优化方式配制的抗逆转录病毒杀微生物剂组合，用于阴道使用和直肠使用，以预防性传播的艾滋病毒感染。该项目包括一系列I期前研究，将同时评估药物代谢动力学、药效学（抗艾滋病毒疗效和毒性）和复合杀微生物剂的可接受性特征。 具体目标1。方法验证。开发并验证血液、组织和腔液中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相容性，并与现有IP/CP资助的实验室交叉验证HIV外植体方法的可比性。 具体目标2。直肠凝胶体积对分布的影响比较I期前研究。比较3.5 mL与10 mL直肠安慰剂凝胶的结肠分布和渗透性，以告知目标3和目标4中I期前临床研究的最终剂量制剂。 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期前临床研究中，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作用、毒理学评估和可接受性。 具体目标4。探索性组合0528/替诺福韦预I期PK/PD/可接受性研究。在一项探索性I期前临床研究中，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。

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.