Research Project
8699499
Project 3, Nonhuman Primates - PK/PD and Efficacy , is responsible under specific aim 1 for the initial in vivo safety evaluation of formulations provided by project 1. Safety evaluations will include the monitoring of adverse events after vaginal and rectal application of candidate formulations. Samples from treated macaques, mucosal fluids, biopsies, and peripheral blood mononuclear cells, will be transferred to core C and project 2 for pharmacokinetic and pharmacodynamic analysis. It is anticipated that several formulations will be evaluated varying volume and API concentration. Distribution of the product and adsorption into tissues will be evaluated by core C from mucosal fluid and biopsy samples collected throuhout the study. Candidates that have been determined to be superior by criteria determined by project 1 and core C will be advanced to efficacy studies, aim 2 of project 3. Aim 2 will utilize the repeat low dose exposure model to evaluate the efficacy of rectal formulations that were deemed superior by PK and PD analysis. Samples taken from the macaques throuhout the efficacy trial will be transferred to project 2 and core C to determine if there is a correlate of protection with PK and/or PD. The repeat low dose exposure model is a rigorous challenge model that can elucidate partial protection from acquisition from full protection from acquisition because of the multiple challenges over several weeks. In addition, data obtained from specific aim 2 will help inform clinical trial design for project 4. The PK and PD data obtained will be critical to the advancement of the formulations into human studies. Specific aim 3 will assess the feasibility of suppositories as a delivery device for pre-exposure prophylaxis. Candidate formulations will be evaluated for distribution, safety, and samples obtained from the macaques will be used to determine the best formulations based on PK/PD parameters described in project 2 and core C.
