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.

项目概要 目前可用的艾滋病毒制剂需要终生、每日给药，并且在长时间使用后， 患者可能会出现服药疲劳，并且经常漏服药物。这可能会产生不利影响 对治疗成功的影响，增加病毒对药物产生耐药性的可能性 用过的。最近，领先制药公司的创新已经证明了长期的潜力。 作用配方使得药物每月只需施用一次（甚至更少），但 在此期间维持药物输送。尽管这有可能极大地影响给药频率， 这种方法的一个主要限制是需要同时组合使用有效的治疗方法 不同的药物，并且仅开发了两种长效制剂的药物。这意味着 患者仍必须每日口服核苷逆转录酶药物片剂 抑制剂（NRTI）。两种工业长效候选药物（利匹韦林 LA 和卡博特韦 LA） 采用研磨工艺制造，该工艺从水溶性差的物质中生成固体药物纳米颗粒 药物。 NRTI 具有固有的水溶性，因此目前与该技术不兼容 被制药公司用来生产长效制剂。利用我们最新的进展 我们建议生成和预测聚合物化学、前药化学、药理学和预测模型 优化由 NRTI 组成的长效骨干方案，以符合当前的护理标准， 与近期的工业发展相得益彰。我们将研究一系列四种 NRTI，并评估其中两种 管理选项将建立长效 NRTI 递送的实用程序并定义新平台 许多水溶性药物的技术。涉及不同学科之间的迭代 合作计划将确保开发出货架稳定的临床相关选项，并发布 NRTI 至少持续一个月。将通过早期安全评估来降低翻译风险。这 还将确定生成的每个候选者的稳健性、其可扩展性、无菌性和成本效益。 为了实现这一雄心勃勃的计划，每位候选人都将接受连续且详细的临床前评估 其药理学和安全性，以优化有利的特性。首席候选人将是 通过数学建模整合实验室数据来选择进行体内分析。我们的战略将 开发长效 NRTI 候选药物并进行概念验证以支持未来的工作并吸引 第三方利益。影响将来自于长效释放的新平台并为患者带来好处 通过简化治疗和给药频率。