Determination of Dosing Concentrations of Formulated APIs using the MTSA

使用 MTSA 确定配方 API 的剂量浓度

• 批准号: 8404125
• 负责人: Robert Walter Buckheit
• 金额: $ 33.75万
• 依托单位: IMQUEST BIOSCIENCES
• 依托单位国家: 美国
• 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/8404125
• 关键词: Address; Algorithms; Biological Assay; CCR5 gene; Cell Culture Techniques; Cells; Clinical; Coitus; Complement; Development; Dose; Drug Kinetics; Epithelial; Evaluation; Event; HIV; HIV vaccine; HIV-1; Immune; In Vitro; Infection; Instruction; Laboratories; Light; Local Microbicides; Methodology; Modeling; Mucous Membrane; Pharmaceutical Preparations; Pharmacodynamics; Philosophy; Process; Production; Rectum; Research; Reverse Transcription; Sterilization; Therapeutic Agents; Thinking; Tissues; Vagina; Virus; Virus Replication; assay development; base; in vitro Assay; in vivo; microbicide; monocyte; novel; prevent; time interval; transmission process

PROJECT SUMMARY (See instructions): In vitro assays used to evaluate the ability of a microbicide to prevent HIV transmission typically utilize models more relevant to the development of anti-HIV therapeutic agents and quantify virus production at short time intervals following infection (3-6 days) using insensitive methodology. To mitigate the shortcomings of these critical biological assays, we have developed a microbicide transmission and sterilization assay (MTSA) to more sensitively and quantitatively evaluate virus transmission in cell culture in the presence of microbicidal compounds. The MTSA defines the concentration of the microbicide required to totally suppress the transmission, replication, and spread of virus in cell culture and may thus help define the effective concentration of the microbicide required to be present in target cells upon delivery in a formulated microbicide product. In light of the difficulty of quantifying the dose of a microbicide product that is required for the delivery of an effective product, it is important to understand how in vitro methodology, complemented with appropriate ex vivo and in vivo pharmacokinetic and pharmacodynamics evaluations, might inform the development process and serve to better define appropriate dosing strategies. Among microbicide developers, the dosing problem is now addressed through the philosophy of

项目摘要（参见说明）： 用于评估杀微生物剂预防 HIV 传播能力的体外测定通常利用与抗 HIV 治疗剂开发更相关的模型，并使用不敏感的方法在感染后短时间内（3-6 天）量化病毒产生。为了减轻这些关键生物测定的缺点，我们开发了一种杀菌剂传播和灭菌测定（MTSA），以更灵敏和定量地评估存在杀菌化合物的细胞培养物中的病毒传播。 MTSA 定义了完全抑制细胞培养物中病毒传播、复制和传播所需的杀微生物剂浓度，因此可能有助于定义在配制的杀微生物剂产品中递送时目标细胞中所需存在的杀微生物剂的有效浓度。鉴于定量提供有效产品所需的杀微生物剂产品的剂量很困难，重要的是要了解体外方法如何辅以适当的离体和体内药代动力学和药效学评估，可以为 开发过程并有助于更好地确定适当的剂量策略。在杀菌剂开发商中，剂量问题现在通过以下理念来解决：