Several studies (ASPIRE, VOICE) have shown that adherence is paramount to the success of HIV prevention methods in women. Providing women with options through alternative drug delivery technologies can positively impact adherence. A compelling strategy includes co-delivery of an anti-HIV agent with a contraceptive agent to prevent pregnancy. This proposal plans to develop a next generation multipurpose prevention technology (MPT) film platform for once a month intravaginal administration of the 4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) prodrug (EFdA-P) and a progestin (levonorgestrel (LNG) or etonogestrel (ENG)) to achieve the dual goal of preventing HIV infection and pregnancy. EFdA-P showed increased bioavailability and tissue permeability compared to the parent EFdA, a highly potent exciting new antiviral drug. This versatile extended release MPT film platform is intended to provide a discrete, low cost and convenient alternative to women at high risk of HIV infection and unintended pregnancy. Recent data from our lab shows that films can deliver an anti-HIV agent in the vagina for up to 1 month even in the context of menses and sexual intercourse. Using this knowledge and our expertise in the development of intravaginal films, this proposal will develop a film platform for co-delivery of a progestin (licensed contraceptive agent) and EFdA-P at a predetermined rate for at least 1 month. MPT films containing EFdA will also be generated for comparison. The R61 phase of this milestone driven proposal will generate critical preformulation data for EFdA/EFdA-P and LNG/ENG drug combinations and optimize the MPT film formulation to achieve one- month delivery of both drugs with desired short-term stability. This phase will also establish the compatibility of film prototype with vaginal tissue and microbial flora in vitro followed by vaginal retention studies in the non- human primate (NHP) model. The R61 phase will demonstrate the ability of the MPT film prototype to attain desired release profiles of both drugs in vivo (NHP model). Using a clearly defined go / no go criteria, a lead MPT film will be transitioned to the R33 phase. The R33 phase will involve IND-enabling activities including drug- drug interaction, in vitro transporter and metabolism studies, manufacturing scale up and establishing long-term stability of the lead MPT film. It will also demonstrate the safety (rat, rabbit, and NHP) and efficacy of the lead MPT film against SHIV infection in NHP model. It will also confirm the ability of the film to function in the context of sexual activity and its ability to deliver contraceptive levels of progestin in the NHP model. The successful completion of proposed work will generate a novel extended release MPT film platform that can be applied to other drug combinations.
The adherence of women to anti-HIV and contraceptives can be improved by providing convenient low-cost alternative product options. This project will develop novel extended release vaginal films that co-deliver anti- HIV and contraceptive agents for one month upon single intravaginal administration.
