Development and Evaluation of Dual Compartment Combination Microbicides

我们建议组建一支在病毒学、毒理学、临床感染性疾病、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学科背景的成熟的研究团队，开发一种可同时用于阴道和结直肠的联合杀微生物剂产品。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。我们的项目将整合产品有效性、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/有效性评估和人类的i期前安全性和PK研究。我们的提案还结合了杀菌剂科学的进步，包括开发一种新的体外方法来确定原料药的剂量水平，扩展到直肠隔室和双隔室产品的行为研究，以及成像和建模，这将增强我们预测配方杀菌剂产品、病毒、生物基质、目标液体和阴道和直肠组织之间相互作用的能力。我们的项目最终将创造有效和可接受的双室使用凝胶（DuoGels）和用于临床开发的固体剂量载体（Smart栓剂）。我们将创造和应用先进的手段来制定和提供这些新的化合物（单独或组合），以生殖分离的方式。追求两种不同的输送方式（双凝胶与智能栓剂）将解释杀微生物剂对HIV-1的功能差异以及女性对产品的不同偏好。产品开发的时间进程将包括确定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协同优化。通过我们与ImQuest制药公司的工业合作伙伴关系，我们的方法和产品将有进一步临床开发的直接出口。

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.