A Pharmacokinetic and Pharmacodynamic Study of an Antibody-based Vaginal Microbi

项目总结(见说明)： 该项目将是第一阶段前的临床先导研究，初步评估一种三价单抗(MAb)局部杀微生物剂的药代动力学、药效学、分布、安全性和可接受性。薄膜剂量形式可使妇女能够早熟地使用它，以方便和迅速地起到保护作用，或者每天使用，这可能更方便，并且由于反复给药，可以提供更好的分布均衡性和生殖道中更高的持续浓度。将评估和比较三种应用策略：单剂量数字插入模拟婚前使用、多日剂量数字应用和使用Duet？的多日剂量应用，Duet？是一种宫颈屏障设备，预计将提供一种易于使用、低成本、可重复使用的方法来应用和保留杀菌剂，同时提供物理屏障来保护脆弱的宫颈。 这两种多日剂量格式将模拟非性交持续应用策略。这将是首次以胶片形式对这些单抗进行临床测试，并将采取预防措施确保研究参与者的安全。为此，暴露参与者的数量和剂量频率将依次递增，我们将使用现有的最敏感的方法(阴道镜检查、局部免疫反应测量、阴道菌群和系统实验室测试监测)来检测杀菌剂的毒性。 该项目的一个创新特点是收集试验参与者的生殖道分泌物，用于进一步的实验室研究，以评估从溶解的膜中提取的单抗与人类宫颈阴道分泌物结合时在阻断艾滋病毒结合方面的效力。

PROJECT SUMMARY (See instructions): 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.