Long acting NRTI therapies for HIV

HIV 长效 NRTI 疗法

• 批准号: 9405658
• 负责人: Caren L. Freel Meyers
• 金额: $ 65.58万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-06 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9405658
• 关键词: AIDS prevention; Anti-Retroviral Agents; Blood Cells; Charities; Chemistry; Clinical; Collaborations; Computer Simulation; Cyclic GMP; Data; Development; Discipline; Disease; Dose; Drug Combinations; Drug Delivery Systems; Drug Kinetics; Drug usage; Ensure; Evaluation; Excision; Fatigue; Formulation; Foundations; Frequencies; Funding; Future; Generations; HIV; HIV therapy; Health; Human; Implant; In Vitro; Individual; Industrialization; Industry; Infection prevention; Injectable; Injection of therapeutic agent; Institution; Integrase Inhibitors; Intellectual Property; Intramuscular; Investments; Laboratories; Lamivudine; Lead; Life; Link; Metabolism; Methodology; Molecular; Non-Prescription Drugs; Nucleosides; Nucleotides; Oral; Oryctolagus cuniculus; Output; Patients; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Pharmacology and Toxicology; Pharmacotherapy; Physiological; Polymer Chemistry; Polymers; Process; Prodrugs; Production; Property; Rattus; Regimen; Reproducibility; Research; Research Activity; Resistance development; Reverse Transcriptase Inhibitors; Risk; Route; Safety; Series; Solid; Sterility; Structure; System; Tablets; Technology; Tenofovir; Time; Translating; Translations; Vertebral column; Virus; Water; Work; base; cell type; chemical function; clinically relevant; cost effectiveness; cytotoxicity; design; drug efficacy; effective therapy; hydrophilicity; implantation; improved; in vivo; innovation; insight; interest; mathematical model; meetings; monomer; multiple drug use; nano; nanomedicine; nanoparticle; non-nucleoside reverse transcriptase inhibitors; novel; novel therapeutics; patient advocacy group; pharmacokinetic model; pill; preclinical evaluation; predictive modeling; programs; species difference; standard of care; success; therapeutic candidate; therapy adherence; therapy development; water solubility

PROJECT SUMMARY Currently available HIV formulations necessitate lifelong, daily dosing and after prolonged periods of time, patients can encounter pill fatigue and frequently miss doses of their medication. This can have detrimental consequences on the success of therapy, increasing likelihood of the virus developing resistance to the drugs used. Recently, innovations by leading pharmaceutical companies have demonstrated the potential for long- acting formulations that enable the drugs to be administered just once a month (or even less frequently) but sustain delivery of drug over that period. Although this has the potential to greatly impact the dosing frequency, a major limitation of this approach is the need for effective treatments to use simultaneous combinations of different drugs, and only two drugs have been developed with long-acting formulations. This means that patients must still take daily oral tablets from a class of drugs known as nucleoside reverse transcriptase inhibitors (NRTIs). The two industrial long-acting therapeutic candidates (rilpivirine LA and cabotegravir LA) were manufactured using a milling process that generates solid drug nanoparticles from poorly water-soluble drugs. NRTIs have inherent water-solubility and are, therefore, currently incompatible with the technologies being utilized by pharmaceutical companies to produce long-acting formulations. Using our recent advances in polymer chemistry, prodrug chemistry, pharmacology and predictive modelling we propose to generate and optimize long-acting backbone regimens consisting of NRTIs to match current standard of care and compliment the recent industrial developments. A series of four NRTIs will be studied and we will assess two administration options that will establish the utility for long-acting NRTI delivery and define a new platform technology for many water-soluble drugs. Iteration between the different disciplines involved within the collaborative program will ensure clinically-relevant options are developed which are shelf-stable, and release NRTIs over at least a one-month period. Translation will be de-risked through early safety evaluation. The robustness of each candidate generated, its scalability, sterility and cost effectiveness will also be established. To deliver this ambitious program, each candidate will undergo a sequential and detailed preclinical evaluation of their pharmacology and safety, to enable optimization of favorable properties. Lead candidates will be selected for analysis in vivo by integrating laboratory data through mathematical modeling. Our strategy will develop candidates for long-acting NRTIs and generate proof-of-concept to support future work and attract third party interest. Impact will derive from a new platform for long-acting release and benefits to patients through simplification of therapies and dosing frequency.

项目摘要 目前可用的艾滋病毒配方需要终生，每日给药，并在长时间之后， 患者可能会遇到药丸疲劳，并经常错过药物的剂量。这可能有害 对治疗成功的后果，增加病毒的可能性增加了对药物的抗药性 用过的。最近，领先的制药公司的创新已经证明了长期的潜力 使药物每月仅一次（甚至频率较低），但 在此期间维持毒品的交付。尽管这有可能极大地影响剂量频率，但 这种方法的主要局限性是需要有效治疗以同时组合 不同的药物，只开发了两种具有长效制剂的药物。这意味着 患者仍然必须从一类称为核苷逆转录酶的药物中服用口服片剂 抑制剂（NRTIS）。两位工业长效治疗候选人（Rilpivirine la和cabo​​tegravir la） 是使用铣削工艺生产的，该工艺从水溶性较差的情况下产生固体药物纳米颗粒 毒品。 NRTI具有固有的水溶性，因此目前与技术不兼容 被制药公司用于生产长效配方。利用我们最近的进步 聚合物化学，前药，药理学和预测建模我们提出生成和 优化由NRTI组成的长效骨干方案，以符合当前的护理标准和 称赞最近的工业发展。将研究一系列四个NRTI，我们将评估两个 将建立长效NRTI交付的实用程序并定义新平台的管理选项 许多水溶性药物的技术。涉及的不同学科之间的迭代 协作计划将确保开发与临床相关的选择，这些选择是固定稳定的，并发布 NRTI至少一个月的时间。翻译将通过早期安全评估降低风险。这 还将确定每个候选者的鲁棒性，其可扩展性，不育和成本效益。 为了提供这个雄心勃勃的计划，每个候选人将接受顺序详细的临床前评估 它们的药理学和安全性，以优化有利的特性。主要候选人将是 通过数学建模整合实验室数据，以在体内进行分析。我们的策略将 培养长效NRTI的候选人，并产生概念验证以支持未来的工作并吸引 第三方利益。影响将源于长效释放的新平台和对患者的好处 通过简化疗法和给药频率。