Determination of Dosing Concentrations of Formulated APIs using the MTSA

项目总结（见说明）： 用于评价杀微生物剂预防HIV传播的能力的体外测定通常利用与抗HIV治疗剂的开发更相关的模型，并使用不敏感方法在感染后短时间间隔（3-6天）定量病毒产生。为了减轻这些关键的生物测定的缺点，我们已经开发了一种杀微生物剂传输和灭菌测定（MTSA），以更灵敏和定量地评估在杀微生物剂化合物存在下细胞培养物中的病毒传输。MTSA定义了完全抑制细胞培养物中病毒的传播、复制和扩散所需的杀微生物剂浓度，因此可以帮助定义在配制的杀微生物剂产品中递送时靶细胞中存在的杀微生物剂的有效浓度。鉴于难以定量递送有效产品所需的杀微生物剂产品的剂量，重要的是要理解体外方法学，辅之以适当的离体和体内药代动力学和药效学评价，如何可以告知 开发过程，并有助于更好地定义适当的给药策略。在杀微生物剂开发者中，剂量问题现在通过以下理念来解决：

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