Compartment-specific topical microbicide formulations

描述（由申请人提供）：为了响应PAR-03-137，本申请是对我们已经资助的IPCP的竞争性补充，即“杀微生物剂开发计划”（MDP）（开始日期：2004年8月1日）。MDP的目标是在第5年底之前在人体1期试验中推出一种外用杀微生物剂产品，其中包括880名受试者的行为和可接受性数据、3项逆转录酶抑制剂（RT）药物猕猴试验的结果以及建立利用外植体技术的药物开发管道。它包括3个项目（临床前/猕猴;行为/可接受性;人类1期试验）和3个核心（行政，法规/数据管理和生物统计学）。所有项目在第1年达到或超过时间轴，并具有完善的核心。补编将说明将特定隔室制剂纳入管道的重要性（上述所有MDP努力都是用阴道制剂）通过（i）进行广泛使用的预备灌肠剂的产品分布、渗透性、吸收和效果的体内研究，（ii）用PMPA和UC-781的结肠特异性制剂进行另外2次猕猴试验，和（iii）第一次进行特异性结肠-配制的杀微生物剂1期试验（UC-781）。该提案的一个关键组成部分是进一步定义风险人群中RAI的行为相关性和候选制剂的可接受性。本申请为3年的补充资金（终止于当前的MDP资助周期），以支持增加2个新的核心（处方开发、外植体质量保证）、1个新项目（项目5：体内处方研究）和显著增加已建立的项目（项目1：临床前/猕猴），并适度补充现有核心以满足增加的使用。增加的内容与最初的IPCP U19的目标一致，即通过建立从体外/离体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管道，对潜在的杀微生物剂化合物进行全面评价。这些发现将增强最初的IPCP目标，并确保提供的产品更具临床相关性，行为上可接受，并为未来的局部杀微生物剂开发奠定基础。

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.