Development and Evaluation of Dual Compartment Combination Microbicides

双室组合杀菌剂的开发与评价

基本信息

批准号：
8494567
负责人：
Robert Walter Buckheit
金额：
$ 357.41万
依托单位：
IMQUEST BIOSCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-22 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8494567
关键词：
Accounting Adherence Anti-Retroviral Agents Attention Behavioral Behavioral Sciences Biological Biological Assay Biomedical Engineering Buffers Characteristics Clinical Colorectal Communicable Diseases Critical Pathways Data Development Disease Dose Drug Formulations Drug Kinetics Environment Evaluation Female Gel HIV HIV Infections HIV-1 Human Image In Vitro Infection Liquid substance Methodology Methods Modality Modeling Osmolar Concentration Perception Pharmacodynamics Pharmacologic Substance Pharmacology Pharmacy (field)Phase Physiology Populations at Risk Property Psychology Rectum Research Personnel Safety Science Sensory Sex Behavior Sexual Partners Solid Sterilization Suppositories Tenofovir Time Tissues Vagina Virus Woman clinical toxicology design dosage efficacy evaluation experience male men microbial alkaline proteinase inhibitor microbicide multidisciplinary non-nucleoside reverse transcriptase inhibitors nonhuman primate novel pandemic disease preference product development programs prophylactic rectal sex transmission process virology

项目摘要

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.

我们建议组建一支在病毒学、毒理学、临床传染病、药理学、药剂学、生理学、心理学/行为科学、材料科学和生物医学工程等领域具有不同多学科背景的完善的研究人员团队，开发一种配制用于交付的组合杀菌剂产品到阴道和结直肠室。合理设计的产品将包括双室凝胶 (DuoGels) 和智能栓剂，它们将作为两种高效抗逆转录病毒药物（替诺福韦和 IQP-0528）的递送载体。我们的计划将整合产品功效、安全性、药代动力学和药效学的体外和离体评估，以及非人类灵长类动物的 PK/PD/安全性/功效评估以及人类的一期前安全性和 PK 研究。我们的提案还结合了杀微生物剂科学的进步，包括开发一种用于确定 API 剂量水平的新型体外方法、扩展到直肠隔室和双隔室产品的行为研究，以及将增强我们预测相互作用的能力的成像和建模配制的杀菌剂产品、病毒、生物基质以及阴道和直肠中的目标液体和组织之间的相互作用。我们的项目最终将创造出有效且可接受的双隔室使用凝胶（DuoGels）和固体剂量载体（智能栓剂）用于临床开发。我们将创造并应用先进的方法，以共离的方式配制和提供这些新型化合物（单独或组合）。对两种不同给药方式（DuoGels 与智能栓剂）的追求将解释针对 HIV-1 的杀菌剂功能的差异以及女性对产品的不同偏好。产品开发的时间过程将包括定义女性和男性可接受性的伴随研究，以便实现生物功能和行为可接受性的共同优化。通过我们与 ImQuest Pharmaceuticals 的工业合作伙伴关系，我们的方法和产品将能够立即用于进一步的临床开发。