Project 6: A Pharmacokinetic and Pharmacodynamic Study of an Antibody-Based Vaginal Microbicide

This project will be a pre-Phase 1 clinical pilot study to make preliminary assessments of the pharmacokinetics, pharmacodynamics, distribution, safety, and acceptability of a trivalent monoclonal antibody (mAb) topical microbicide delivered as a vaginally-inserted film. The film dosage format may enable women to use it either precoitally, for convenience and rapid onset of protection, or daily, which may be more convenient, and due to repeated dosing, could provide superior evenness of distribution and higher sustained concentrations in the genital tract. Three application strategies will be assessed and compared: single-dose digital insertion modeling precoital use, multiple-daily-dose digital, and multiple-daily-dose application using Duet®, a cervical barrier device expected to provide an easy to use, low cost, reusable means to apply and retain microbicides, while providing a physical barrier to protect the vulnerable cervix. The two multiple daily dose formats  will model  non-coital continual application strategies. These will be the first clinical tests of these mAbs in film format, and precautions will be taken to assure the safety of study participants. To this end, there will be sequential escalation of the number of exposed participants and dose frequency, and we will employ the most sensitive methods available (colposcopy, measures of local immune response, vaginal flora, and systemic laboratory test monitoring) to detect microbicide toxicities.

An innovative feature of this project will be the collection of genital tract secretions from trial participants for further laboratory studies to assess the potency of mAbs from the dissolved film in blocking HIV binding when combined with human cervicovaginal secretions.

Specific Aims:

Specific Aim 1.  Evaluate the pharmacokinetic and pharmacodynamic properties, and make preliminary safety and acceptability observations on a single digital insertion of a topical trivalent mAb microbicide film. Blood and cervicovaginal specimens will be tested for mAb concentrations, and the cervicovaginal specimens assessed for ex vivo viral neutralizing activity, changes in innate host immune defense molecules, and proinflammatory cytokines. Sampling for antibody at multiple discrete sites will allow assessment of uniformity of distribution. Additional safety endpoints will include colposcopy, assessment of quantitative changes to vaginal microflora, and laboratory safety measurements to rule out renal, hepatic, coagulation and other hematological effects of potentially absorbed antibody.

Specific Aim 2. Evaluate the pharmacokinetic and pharmacodynamic properties, and make preliminary safety and acceptability observations on multiple digitally-inserted, daily doses of the mAb film.  Assessments will be as in Specific Aim 1. In addition the hypothesis will be tested that multiple daily doses will provide higher and more evenly distributed levels of antibodies in cervicovaginal mucus, assessed by comparison with results in Specific Aim 1.      

Specific Aim 3. Evaluate the pharmacokinetic and pharmacodynamic properties, and make preliminary safety and acceptability observations on multiple, daily doses of the mAb film, applied and retained using the Duet® cervical barrier and microbicide application device. Assessments will be as in Specific Aim 1. In addition, these observations, when compared to results in Specific Aim 2, will provide a preliminary test of the hypothesis that the Duet device will increase retention of antibodies in the genital tract, and provide an acceptable and convenient microbicide applicator and cervical barrier.