Long Acting Injectable Depots for TB Therapy

项目概要/摘要 复杂的药物治疗方案和当前结核病药物的持续时间长，常常会影响患者的服药依从性 疗法。在许多社会和全球环境中，这些挑战在患者的环境中更加严重，其中 结核病与艾滋病毒阳性患者的联合治疗受到侮辱。因此，长效给药产品应该发挥作用 对提高患者依从性、提高药物疗效具有重要作用。该项目将开发一个新的 可注射的储库技术，可满足包括多月交付在内的一般目标产品概况 从单次注射、低容量和低粘度制剂到减少患者疼痛、组合用药 根据需要制定配方，具有可设计的 PK 曲线的持续药物释放，最小的初始和耗尽爆发 释放以提高安全性并防止耐药性，并且对于全球环境而言，商品成本低并降低了 冷链要求。该仓库技术还具有重要的转化产品属性： 简化 CMC 和 cGMP 制造，可以更快地取得临床开发成果。一个 将开发用于结核病治疗的新注射储库产品，该产品不同于目前基于分散的产品 配方方法是完全合成的储存库。该提案围绕 2 个具体目标构建 R61阶段和R33阶段的两个进一步目标：（1）通过合成化学制备的前药单体是 在第二个合成步骤中直接聚合，以创建含有药物的“drugamer”储库疗法 进入仓库本身。与目前的分散制剂方法相比，药物分子表现出更高的药物 装载效率、共同配制不同亲脂性药物的能力以及线性、可单独定制 PK 配置文件可最大限度地减少第一周和最后一周的突发释放。这些 PK 配置文件在动力学上由 与单个药物相关的接头特性以及聚合物结构设计。这一目标将利用 CSIRO 墨尔本独特的高通量聚合物库和筛选平台，用于识别铅注射剂 使用贝达喹啉和莫西沙星作为初始药物示例进行储库设计。精密 LC-MS/MS PK 表征将与 PK/PK 建模一起评估持续的 PK 概况。 (2)演进与优化 通过初始结核病模型中的功效来确定先导候选药物，从而实现更高通量的成像 活动的表征。随后将进行 Mtb 模型评估并选择领先车厂 候选人； (3) 在 A/BSL3 Mtb 模型中测试和优化两个先导候选药物，按照以下标准 PK/PD、功效和剂量依赖性以及给药持续时间。铅仓库的特点还在于 加速稳定性研究，以测试它们是否可以避免冷链储存。 (4) 评估迭代上选 混合优化的贝达喹啉和莫西沙星长效制剂的组合长效制剂，包括双重 PK 分析和 PK/PD 建模。同样的方法也可以扩展到开发未来的治疗方法 基于其他组合药库设计的产品。这些有利的平台属性激发了这一点 项目作为抗结核患者产品库的潜在新成员。

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.