Drug at the Right Place & Concentration: Optimizing Combination Vaginal Ring PrEP

药物在正确的地方

• 批准号: 8988532
• 负责人: Betsy C. Herold
• 金额: $ 265.22万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-18 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8988532
• 关键词: AIDS prevention; Address; Adherence; African; Age; Anti-Retroviral Agents; Antiviral Agents; Biological Factors; Cervical; Clinical; Clinical Research; Conflict (Psychology); Data; Development; Dose; Drug Kinetics; Environment; Equilibrium; Exhibits; Formulation; Fumarates; Future; Genital system; Goals; HIV; HIV Infections; HIV risk; High Risk Woman; Human; Infection; Knowledge; Lymphoid Tissue; Modeling; Oral; Outcome; Pharmaceutical Preparations; Pharmacodynamics; Phase; Physiological; Predisposition; Prodrugs; Prophylactic treatment; Protective Agents; RNA-Directed DNA Polymerase; Risk; Seminal fluid; Site; Tenofovir; Testing; Tissues; Translating; Vagina; Vaginal Ring; Woman; cohort; design; hormonal contraception; inhibitor/antagonist; microbiota; nonhuman primate; novel; pandemic disease; pharmacodynamic model; pre-clinical; programs; rectal; tissue/cell culture

The HIV pandemic and its burden on women highlights the urgent need for effective pre-exposure prophylaxis (PrEP). We hypothesize that the optimal strategy will require combining potent antiretroviral (ARV) drugs that are active in multiple compartments (vaginal, cervical, and rectal), exhibit rapid and sustained pharmacokinetics (PK), are effective against multiple clades, and are safe. Ideally, sustained delivery formulations should be prioritized, as adherence to daily or coitally dependent dosing has proven difficult. Building from these concepts, this Integrated Preclinical/Clinical Program will focus on intravaginal ring (IVR) delivery of tenofovir disoproxil fumarate (TDF), the more potent prodrug of tenofovir (TFV), in combination with maraviroc, an entry inhibitor, or with IQP-0528, a non-nucleoside reverse transcriptase and entry inhibitor that we have successfully formulated for IVR delivery. We will also study GS7340, a newer TFV prodrug in development, with potentially better distribution into lymphoid tissues. The conflicting results of recent topical and oral PrEP trials highlight the complexities in translating preclinical data into real world use. The variable clinical outcomes may reflect differences in dosing (coitally dependent vs. daily) or in adherence. However, other important biological factors, including age, hormonal contraception, semen and vaginal microbiota may have acted on the genital mucosal environment to alter drug PK, antiviral activity (pharmacodynamics (PD)), and susceptibility to HIV, shifting the balance between protection and infection. To address this critical knowledge gap, we propose intensive PK/PD studies in non-human primates (Project 1) and exploratory clinical studies in well-characterized cohorts of U.S. and sub-Saharan African women to assess how clinical variables modulate drug PK/PD using novel ex vivo cell and tissue culture models (Projects 2 and 3), supported by a bioanalytical scientific core. Our goal is to optimize sustained IVR delivery of an ARV combination that will provide protective drug levels at the sites of HIV infection in high risk women. We will test a PK/PD model in a pre-Phase I TDF IVR study in women at risk for HIV acquisition. Results obtained will enable us to optimize IVR combinations for future clinical studies.

艾滋病毒大流行及其对妇女造成的负担突出表明迫切需要有效的预先接触