Long Acting Injectable Depots for TB Therapy

项目摘要/摘要 患者的服药依从性经常受到当前结核病药物复杂的药效和较长疗程的影响 治疗。这些挑战在许多社会和全球环境中的患者环境中加剧 结核病与艾滋病毒阳性患者的联合治疗被污名化。因此，长效给药产品应该发挥作用 对提高患者依从性和提高药物疗效具有重要作用。这个项目将开发一种新的 可注射仓库技术，可满足包括数月交货的一般目标产品配置文件 从单针、小容量、低粘度的配方来减轻患者的痛苦，联合用药 必要时的配方，具有可设计的PK曲线的持续药物释放，最小的初始和超时爆发 释放，以增加安全性和防止抗药性，并为全球设置具有低商品成本和降低 冷链要求。这项仓库技术还具有以下重要的翻译产品属性 简化CMC和cGMP制造，可带来更快的临床开发成就。一个 将开发用于结核病治疗的新的可注射仓库产品，该产品不同于现有的分散剂 配方的方法是成为一个完全合成的仓库。这项提案是围绕 R61阶段和R33阶段的两个进一步目标：(1)合成化学合成的前药物单体是 在第二个合成步骤中直接聚合，以创建具有药物构建的“药物玩家”库疗法 进入仓库本身。与目前的分散制剂方法相比，药物玩家表现出更高的药物 加载效率，能够共同配制不同脂类的药物，以及线性的、单独可裁剪的 PK配置文件，最大限度地减少第一周和最后一周的突发释放。这些PK配置文件由 与单个药物捆绑在一起的连接物属性，以及聚合物结构设计。这一目标将利用 CSIRO墨尔本独一无二的高通量聚合物文库和筛选平台用于鉴定可注射的铅 Depot设计使用贝达奎兰和莫西沙星作为最初的药物例子。复杂的LC-MS/MS PK 特征化将评估持续的PK配置文件以及PK/PK建模。(二)进化优化 Depot通过在允许更高吞吐量成像的初始结核病模型中的有效性来领导候选对象 对活动的表征。随后将对MTB模型进行评估，并将其选择到销售线索仓库 (3)在A/BSL3Mtb模型中对两个主要药库候选者进行测试和优化，标准为 PK/PD、疗效和剂量依赖关系、给药持续时间。铅仓库的特征也将在 加速稳定性研究，以测试它们是否可以避免冷链储存。(4)向上迭代求值-选中 混合优化贝达奎林和莫西沙星车辆段的联合车辆段，包括双PK 剖析和PK/PD建模。这种相同的方法也可以扩展到未来的治疗方法 产品以其他组合药库设计为基础。这些有利的平台属性推动了这一点 该项目是抗结核患者产品系列中潜在的新成员。

PROJECT SUMMARY/ABSTRACT Patient dosing adherence is often compromised by the complex pill regimes and long duration of current TB drug therapies. These challenges are exacerbated in settings for patients in many social and global settings where TB co-therapy with HIV positive patients is stigmatized. Long-acting drug delivery products should therefore play an important role to increase patient adherence and increase drug efficacy. This project will develop a new injectable depot technology that address a general target product profile that includes multiple-month delivery from a single injection, low volume and low viscosity formulations to reduce patient pain, combination drug formulation where required, sustained drug release with designable PK profiles, minimal initial and run-out burst release to increase safety and prevent drug resistance, and for global settings has low cost of goods and lowered cold-chain requirements. This depot technology also has the important translational product attributes of streamlined CMC and cGMP manufacturing that could lead to more rapid clinical development achievement. A new injectable depot product for TB therapy will be developed that is differentiated from current dispersal based formulation approaches by being a fully synthetic depot. The proposal is structured around 2 specific aims in the R61 phase and two further aims in the R33 phase: (1) Prodrug monomers made by synthetic chemistry are directly polymerized in a second synthetic step to create “drugamer” depot therapeutics that have the drugs built into the depot itself. Compared to current dispersion formulation approaches, the drugamers exhibit higher drug loading efficiencies, the ability to co-formulate drugs of different lipophilicities, and linear, individually tailorable PK profiles that minimize first- and last-week burst release. These PK profiles are kinetically controlled by the linker properties that are tied to the individual drugs, along with polymer architectural design. This aim will exploit a unique high throughput polymer library and screening platform at CSIRO Melbourne to identify lead injectable depot designs using bedaquiline and moxifloxicin as initial drug examples. Sophisticated LC-MS/MS PK characterization will assess the sustained PK profile together with PK/PK modeling. (2) Evolve and optimize depot lead candidates through efficacy in an initial TB model that allows higher throughput imaging characterization of activity. This will be followed by an Mtb model assessment and selection to a lead depot candidate; (3) Test and optimize the two lead drug depot candidates in an A/BSL3 Mtb model, by the criteria of PK/PD, efficacy and dose dependence, and dosing duration. The lead depot will also be characterized in accelerated stability studies to test whether they can avoid cold-chain storage. (4) Evaluate iterated up-selected depots in combination depots from mixing optimized bedaquiline and moxifloxacin depots, including dual PK profiling and PK/PD modeling. This same approach could also be expanded to develop future therapeutic products based on other combination drug depot designs. These favorable platform attributes motivate this this project as a potential new addition to the repertoire of anti-TB patient products.