Combination HIV Prevention in Drug-Eluting Fibers:  Designing for Efficacy and Use

Dorothy L Patton, PhD, Co-Investigator, with Kim Woodrow, PhD, Principal Investigator

We have developed an innovative dosage form for vaginal drug delivery using polymeric fibers fabricated by electrospinning. Drug-eluting fibers exhibit unique materials and processing features that distinguish them from existing microbicide products. Our work to date has shown the versatility of polymer fibers for rapid and sustained delivery of diverse ARV drugs alone and in combination, to fabricate composite materials of varying microstructure, and to be produced using a manufacturing scale electrospinning process. However, the further advancement and development of any single microbicide drug delivery system must prioritize that the product embody physical attributes that impact user perceptions without compromising the design for biological efficacy. While our previous results advance the concept of using drug-eluting fibers as a new dosage form for topical delivery of combination ARV drugs for HIV prevention, the feasibility of this new platform technology to be designed for chemoprophylactic protective efficacy against vaginal HIV challenge while exhibiting bulk material properties with adequate user perceptibility (geometry, texture, dissolution time and viscosity) has not been demonstrated. We propose here a project framework to inform the design of a first-generation, fiber-based, topical microbicide that is constrained for functions prioritized from user perception and NHP safety/PK studies. This proposal integrates three primary research areas:
1) fiber DDS prototype design and formulation
2) user-guided product design and evaluation, and
3) NHP safety/PK and efficacy testing
Our framework is an iterative process to design, test and select lead candidate fiber DDS prototypes that are optimized for user perceptions (Aim 1) and biological safety/PK (Aim 2), before advancing to a vaginal challenge efficacy study in NHPs (Aim 3). We selected a novel triple ARV drug combination to demonstrate the strength of the fiber DDS to deliver agents that are physico-chemicaly diverse, having differing mechanisms of action against HIV, and show instantaneous inhibitory potential in combination to halt virus replication. We also propose to design fiber fabrics that modulate drug release for both pericoital and sustained protection. Finally, we incorporate incisivie product acceptability studies early in the preclinical deelopment of a new microbicide product to help guide the design of the formulation's biophysical and other attributes to have the greatest impact on user adherence. These studies will be the first to confirm that fiber-based microbicides can be designed to prioritize physical properties that are critical to the user experience, while at the same time prioritizing functional properties that prevent vaginal HIV infection. The broader impact of these innovations will support the rapid advancement of a fiber microbicide to first-in-human clinical trials.

Funding Source: National Institutes of Health (NIH/NIAID)
End Date: 1-31-18

Project 2: Nonhuman Primate Studies of Tenofovir and Dapivirine

Dorothy L Patton, PhD, Principal Investigator

The revised aims are: 1) Determine optimal dosing level of TFV in film formulation in the nonhuman primate. Hypothesis: The drug release rate will be greater from the film formulation as compared to the gel formulation. 2) Perform product distribution and transport studies. Hypothesis: Vaginal film formulations will distribute throughout the lower genital tract as efficiently as vaginal gel formulation. 3) Describe the pharmacokinetics (PK) of film vs gel formulations of tenofovir and dapivirine. Hypothesis: TFV and dapivirine will be present in secretions, cells and tissues throughout the cervicovaginal site. Tenofovir will be detected in blood sera, dapivirine will not. 4) Employ the nonhuman primate safety model to help guide formulation optimization (Project 1, Core C) via vaginal safety measures. Hypothesis: Film formulations will be shown to have acceptable safety profiles. Intrinsic antibacterial activity will be minimally disrupted by film formulations.

Funding Source: National Institutes of Health (NIH/NIAID)
End Date: 5-31-17

Systems and Carcinogenic Impact Assessment of Topical Microbicides on the Human Mucosa

Florian Hladik, MD, PhD, Principal Investigator

Several drugs, including NRTIs like tenofovir, and non-NRTIs like dapivirine, are being tested for vaginal or rectal application to prevent sexual HIV transmission. However, NRTI drugs have side effects that could undermine their effectiveness and cause serious safety concerns with long-term, topical use. In this proposal, we study these side effects with a particular focus on tenofovir's possibly carcinogenic effects at the currently-tested concentrations, and determine whether non-NRTIs could be a safer alternative.

Funding Source: National Institutes of Health (NIH/NIAID)
End Date: 4-30-20

Film Antiretroviral Microbicide Evaluation

Dorothy L Patton, PhD, Principal Investigator

The broad objective of the Nonhuman Primate Core is to support the development of optimized formulations(s) for microbicide/biomedical prevention (MBP) delivery that result in reliable administration and sustained drug presence at specified target sites. Macaque models will be utilized to determine the pharmacokinetics of MK-2048 when delivered in an extended release vaginal film, to establish the safety profile for film use in the presence and absence of coitus, and to assess the developed product’s efficacy in preventing HIV infection.

Funding Source: Magee-Womens Hospital
End Date: 5-31-20