We propose to bring a well-established team of Investigators with diverse multidisciplinary backgrounds in virology, toxicology, clinical infectios disease, pharmacology, pharmaceutics, physiology, psychology/behavioral science, materials science, and biomedical engineering to develop a combination microbicide product formulated for delivery to both the vaginal and the colorectal compartments. The rationally designed products will include dual compartment gels (DuoGels) and Smart Suppositories that will function as delivery vehicles for two highly potent antiretroviral agents - tenofovir and IQP-0528. Our program will integrate in vitro and ex vivo evaluations of product efficacy, safety, pharmacokinetics and pharmacodynamics, as well as PK/PD/safety/efficacy evaluations in nonhuman primates and pre-Phase 1 safety and PK studies in humans. Our proposal also incorporates advancements in microbicide science, including the development of a novel in vitro method for determination of API dosing levels, behavioral studies extended to the rectal compartment and dual compartment products, and imaging and modeling that will enhance our ability to predict the interactions between formulated microbicide products, virus, biological matrices, and target fluids and tissue in the vagina and rectum. Our project will culminate in the creation of effective and acceptable, dual compartment use gels (DuoGels) and solid dosage vehicles (Smart Suppositories) for clinical development. We will create and apply advanced means to formulate and deliver these novel compounds (alone or in combinations) in coitally-dissociated ways. Pursuit of the two different delivery modalities (DuoGels versus Smart Suppositories) will account for both differences in microbicide functionality against HIV-1 and different product preferences amongst women. The time course of product development will include concomitant studies that define acceptability to women and men, so that cooptimization of biological functionality and behavioral acceptability is achieved. Through our industrial partnership with ImQuest Pharmaceuticals our methodology and products will have an immediate outlet to further clinical development.

Public Health Relevance

We propose to develop and evaluate the first safe, effective and user-acceptable dual compartment microbicide. Given that over 90% of HIV infections occur as a function of unprotected rectal or vaginal intercourse, having a single product that targets both compartments, reduces infections across a range of sexual activities, reduces infections across all at-risk populations, and is usable by same-sex and opposite sex partners will have a significant impact on the HIV pandemic.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-ESB-A (M2))
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Turpin, Jim A
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Imquest Biosciences
United States
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Weld, Ethel D; Hiruy, Hiwot; Guthrie, Kate Morrow et al. (2017) A Comparative Pre-Phase I Study of the Impact of Gel Vehicle Volume on Distal Colon Distribution, User Experience, and Acceptability. AIDS Res Hum Retroviruses 33:440-447
Ham, Anthony S; Buckheit Jr, Robert W (2017) Designing and developing suppository formulations for anti-HIV drug delivery. Ther Deliv 8:805-817
Katz, David F; Yuan, Andrew; Gao, Yajing (2015) Vaginal drug distribution modeling. Adv Drug Deliv Rev 92:2-13
Pereira, Lara E; Mesquita, Pedro M M; Ham, Anthony et al. (2015) Pharmacokinetic and Pharmacodynamic Evaluation following Vaginal Application of IQB3002, a Dual-Chamber Microbicide Gel Containing the Nonnucleoside Reverse Transcriptase Inhibitor IQP-0528 in Rhesus Macaques. Antimicrob Agents Chemother 60:1393-400
Gao, Y; Yuan, A; Chuchuen, O et al. (2015) Vaginal deployment and tenofovir delivery by microbicide gels. Drug Deliv Transl Res 5:279-94
Ham, Anthony S; Nugent, Sean T; Peters, Jennifer J et al. (2015) The rational design and development of a dual chamber vaginal/rectal microbicide gel formulation for HIV prevention. Antiviral Res 120:153-64