Long Acting Injectable Depots for TB Therapy

用于结核病治疗的长效注射剂

• 批准号: 10632118
• 负责人: Patrick S. Stayton
• 金额: $ 63.48万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-22 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10632118
• 关键词: Acceleration; Achievement; Acute; Address; Adherence; Antitubercular Agents; Architecture; Attenuated; Automation; Chemistry; Clinical; Clinical Trials; Cold Chains; Combination Drug Therapy; Complex; Cyclic GMP; Data; Dependence; Development; Dimethyl Sulfoxide; Dose; Drug Combinations; Drug Delivery Systems; Drug Formulations; Drug Interactions; Drug resistance; Exhibits; Formulation; Freeze Drying; Future; HIV; HIV Seropositivity; HIV therapy; HIV/TB; High Prevalence; Image; Impairment; Implant; Individual; Infection; Injectable; Injections; Kinetics; Lead; Length; Libraries; Machine Learning; Maps; Modeling; Moxifloxacin; Mycobacterium tuberculosis; Pain; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase; Plasma; Play; Polymer Chemistry; Polymers; Powder dose form; Prodrugs; Property; Refrigeration; Regimen; Robotics; Role; Running; Safety; Solubility; Stigmatization; Structure; Synthesis Chemistry; Technology; Testing; Therapeutic; Time; Tissues; Translations; Virulent; Viscosity; Water; Weight; biosafety level 3 facility; chronic infection; clinical development; co-infection; compliance behavior; cost; design; drug action; drug efficacy; drug release profile; experience; first-in-human; improved; innovation; lead candidate; lipophilicity; manufacture; monomer; mouse model; multidisciplinary; new technology; pharmacokinetics and pharmacodynamics; pill; prevent; product development; screening; social; solid state; therapy duration; tuberculosis drugs; tuberculosis treatment

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.

项目摘要/摘要 复杂的药丸制度和当前结核病药物的持续时间通常会损害患者给药的依从性 疗法。这些挑战在许多社会和全球环境中的患者的环境中加剧了 与HIV阳性患者共同治疗结核病受到污名。因此，长效药物输送产品应发挥 提高患者依从性和提高药物效率的重要作用。这个项目将开发一个新的 可注射的存款技术，该技术涉及包括多个月交货的一般目标产品配置文件 从单一注射，低体积和低粘度配方来减轻患者疼痛，联合药物 在需要的情况下形成，持续的药物释放，具有设计的PK剖面，最少的初始和淘汰的爆发 释放以提高安全性并防止耐药性，对于全球环境，商品成本较低并降低 冷链要求。该仓库技术还具有重要的翻译产品属性 简化的CMC和CGMP制造可能会导致更快的临床发展成就。一个 将开发用于结核病治疗的新注射沉积物，与当前的基于分散区分开 形成是通过完全合成沉积物来接近的。该提案是在两个特定目标中构成的 R61相和在R33阶段进一步的两个目标：（1）合成化学制造的前药单体是 直接在第二个合成步骤中直接聚合，以创建“药物调理器”沉积疗法，并建立了药物 进入存款本身。与当前的分散公式方法相比，吸毒者暴露了更高的药物 加载效率，能够共同成型的不同亲脂性的药物以及线性的，可定制的线性 PK概况最小化了第一周和最后一周的爆发。这些PK轮廓由 与各个药物相关的接头特性以及聚合物架构设计。这个目标将利用 CSIRO墨尔本的独特高吞吐量聚合物库和筛选平台，以识别可注射铅 仓库使用Bedaquiline和Moxifloxicin作为初始药物示例进行设计。精致的LC-MS/MS PK 表征将与PK/PK建模一起评估持续的PK曲线。 （2）进化和优化 在初始结核病模型中，通过效率通过效率来促进更高的吞吐量成像 活动的表征。随后将进行MTB模型评估，并选择铅矿床 候选人; （3）按照A/BSL3 MTB模型测试并优化两个铅药物库候选物 PK/PD，有效性和剂量依赖性以及剂量持续时间。铅仓库也将在 加速稳定性研究以测试它们是否可以避免冷链存储。 （4）评估迭代的上推定 混合优化的Bedaquiline和Moxifloxacin沉积物中的组合沉积物中的沉积物，包括双PK 分析和PK/PD建模。这种方法也可以扩展以开发未来的治疗 基于其他组合药物仓库设计的产品。这些有利的平台属性激励这个 项目是抗TB患者产品曲目的潜在新成员。