Compartment-specific topical microbicide formulations

说明(申请人提供)：为响应PAR-03-137，本申请是对我们已经资助的IPCP的竞争性补充，即“杀微生物剂发展计划”(MDP)(开始日期：8/1/04)。MDP承诺的目标是在第5年年底之前将一种局部杀微生物剂产品用于人类第一阶段试验，获得880名受试者的行为和可接受性数据，3次逆转录酶抑制剂(RT)药物的猕猴试验结果，并利用外植体技术建立药物开发流水线。它包括3个项目(临床前/猕猴；行为/可接受性；人类第一阶段试验)和3个核心(行政、监管/数据管理和生物统计学)。所有项目都在第一年之前达到或早于时间表，并拥有完善的核心。该补充剂将致力于将特定隔室配方纳入准备上市的重要性(上述所有MDP努力都是针对阴道配方)，方法是：(1)对广泛使用的预备灌肠的产品分布、渗透性、吸收和疗效进行体内研究；(2)再用PMPA和UC-781进行2项针对结肠的恒河猴试验；(3)首次进行针对结肠的杀微生物剂1期试验(UC-781)。该提案的一个关键组成部分是进一步定义高危人群中RAI的行为相关性以及候选配方的可接受性。这项申请是为期3年的补充资金(终止于当前的MDP供资周期)，以支持增加2个新核心(配方开发、外植体质量保证)、一个新项目(项目5：体内配方研究)和对一个已有项目(项目1：临床前/猕猴)进行重大扩充，同时适度补充现有核心以满足增加的使用。这些增补与最初的IPCP U19‘S的目标一致，即通过建立从体外/体外结肠外植体研究到体内动物疗效和人体安全性试验的临床前开发流程，对潜在的杀微生物剂化合物进行全面评估。这些发现将增强IPCP最初的目标，确保提供的产品(S)更具临床相关性、行为可接受性，并为未来局部杀微生物剂的开发奠定基础。

DESCRIPTION (provided by applicant): In response to PAR-03-137, this application is in the form of a Competitive Supplement to our already funded IPCP, the "Microbicide Development Program" (MDP)(start date: 8/1/04). The MDP has committed goals of having one topical microbicide product in human Phase 1 trials by the end of Year 5, with behavioral and acceptability data from 880 subjects, results from 3 macaque trials of reverse-transcriptase inhibitor (RT) agents and the establishment of a drug development pipeline utilizing explant technology. It consists of 3 Projects (Preclinical/Macaque; Behavioral/Acceptability; Human Phase 1 trials) and 3 Cores (Administrative, Regulatory/Data Management & Biostatistics). All Projects are at or ahead of Timeline by Year 1 with well- established Cores. The Supplement will address the importance of incorporating compartment-specific formulations into the pipeline (all MDP efforts above are with vaginal formulations) by (i) conducting in vivo studies of product distribution, permeability, absorption and effects of widely used preparatory enemas, (ii) performing 2 additional macaque trials with colon-specific formulations of PMPA and UC-781 and (iii) be the first to conduct a specifically colon-formulated microbicide Phase 1 trial (UC-781). A critical component of the proposal is to further define the behavioral correlates of RAI in at-risk populations and the acceptability of candidate formulations. This application is for 3 years of supplemental funding (terminating with the current MDP funding cycle) to support the addition of 2 new Cores (Formulation Development, Explant Quality Assurance), one new Project (Project 5: in vivo Formulation Studies) and significant augmentation of an established Project (Project 1: Pre-clinical/Macaque), with moderate supplementation of existing Cores to meet increased use. The additions are consistent with the original IPCP U19's Aims to undertake a comprehensive evaluation of potential microbicide compounds through the establishment of a preclinical development pipeline from in vitro/ex vivo colonic explant studies through to in vivo animal efficacy and human safety trials. These findings will augment the initial IPCP's goals and ensure that the product(s) delivered are more clinically relevant, behaviorally acceptable as well as lay the foundation for future topical microbicide development.