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. ? ? ? ?
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