Highly Active Antiretroviral Therapy (HAART), where antiretroviral (ARV) drugs are given in combination, has become the standard in treatment of HIV/AIDS. There is growing consensus that combinations of ARV drugs will be essential for an optimally effective non-vaccine biomedical prevention (nBP) product against HIV. The overarching goal of this IPCP-MBP is to develop intravaginal ring (IVR) formulations based on ARV combinations for prevention of sexual HIV transmission, emphasizing the needs of women in the developing world. A number of obstacles have thus far prevented the development of a safe and effective topical combination nBP product, including: lack of an reliable screening process to select an optimal combination; difficulty in formulating combinations for topical delivery; long timelines to advance novel candidates through the clinical trial phase; concern with manufacturability and manufacturing scale-up for complex delivery platforms; and issues with adherence confounding determination of efficacy and safety in clinical trials. This Program, consisting of 5 Projects and 2 Cores, aims to overcome these obstacles by applying an innovative strategy to advance a library of multidrug IVRs through a systematic and rational screening pipeline. An initial lead combination of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) will undergo a (pre-Phase I) Exploratory Clinical Trial (Project 4) in healthy women to assess pharmacokinetics (Project 1), safety (Project 2), and surrogate efficacy (Project 3). Concurrently, the TDF-FTC lead and 8 alternative ARV IVR formulations will be assessed in a novel screening process using quantitative metrics to select the best-performing candidate, in terms of safety and efficacy, using well-defined, quantitative go/no-go criteria. Methods and capacity to manufacture clinical cGMP lots of the best-performing combination IVR will be developed in the IND-enabling critical path Project (Project 5), allowing rapid advancement of the safest and most efficacious candidate into Phase I clinical trials at the conclusion of the IPCP. The parallel screening and clinical approach accelerates transition of the final lead to post-IPCP Phase I clinical trials: If TDF-FTC is selected, the IND- enabling critical path is completed within the IPCP and Phase I trials can begin; if an alternative combination is selected, the manufacturing and clinical procedures are in place for rapid advancement of the final, safest and most efficacious lead combination IVR into Phase I clinical trials. Successful completion of this work is of exceptional significance because it uses a systematic, scientific pipeline strategy, based on clear, quantitative decision points, for the accelerated, rational development of a lead combination ARV IVR for HIV prevention, and mitigates against learning, years later, that combinations other than TDF-FTC should have been advanced.
The proposed Program's long-term goal is to empower women to protect themselves from HIV infection. A novel, iterative evaluation process using quantitative metrics will be used to rationally select the safest and most efficacious candidate from a library of antiretroviral combinations formulated in a novel intravaginal ring platform. These efforts form an IND-enabling critical path to rapidly advance the best candidate into post-IPCP Phase I clinical trials, ultimately, leading to a safe and effective topical non-vaccine biomedical prevention product for preventing sexual HIV infection. Project 1: Pharmacokinetics of Combination Antiretroviral Intravaginal Rings Project Leader (PL): Hendrix, C. Description (provided by applicant): The failure to establish proof-of-concept in several clinical trials for the prevention of sexual HIV transmission using microbicides, and the highly complex environment for non-vaccine biomedical prevention (nBP) development and product use underscores the pressing need for an improved understanding of the fundamental processes at work. A theoretical conceptualization of host, drug, and virus interactions can inform the construction of a mechanistic pharmacokinetic-pharmacodynamic (PK-PD) model to support rational nBP development. For topical vaginal delivery, a PK-PD model must encompass the anatomic 'compartments' where the drug and virus distribute. An understanding of drug concentrations over time in these compartments is critical in the development of a useful PK model where knowledge of dosing regimen and concentration in one compartment allows estimation of concentration in another compartment, without additional sampling. The Program's long-term goal is to develop intravaginal ring (IVR) formulations of multiple antiretroviral (ARV) agents for prevention of sexual HIV infection, emphasizing the needs of women in the developing world. The objective of this application is to quantitatively explore the PK domain in animals and humans receiving IVRs formulated with combinations of up to three ARV drugs by sampling of up to 6 different compartments within the body. In Aim 1, assays will be developed and validated for all studied ARV drugs in the 6 target compartments (fluid and CD4+ cell components, where relevant, within the cervicovaginal secretions, tissues, and blood). The PK for optimized IVR formulations will be determined in mice, sheep, macaques, and humans in a (pre-Phase I) Exploratory Clinical Trial (Project 4). In Aim 2, the spatiotemporal drug concentration data gathered will be evaluated in light of PD outcomes, both efficacy (Project 3) and toxicity (Project 2): ex vivo, in a novel 3D vaginal epithelial cell (VEC) culture model; in vio, in sheep (toxicity only), humanized mice, and macaques; and humans (Project 4) for toxicity and surrogate efficacy. The results will be used to develop exploratory PK-PD models to describe the drug exposure-response relationships for each of the candidate ARV IVR formulations tested. In Aim 3, the role of membrane transporters and metabolizing enzymes in the vaginal epithelium on drug disposition and potential drug-drug interactions will be investigated ex vivo using our VEC culture system and samples collected as part of the above in vivo studies.
