Long acting NRTI therapies for HIV

HIV 长效 NRTI 疗法

• 批准号: 10172835
• 负责人: Caren L. Freel Meyers
• 金额: $ 54.98万
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10172835
• 关键词: AIDS prevention; Anti-Retroviral Agents; Blood Cells; Charities; Chemistry; Clinical; Collaborations; Cyclic GMP; Data; Development; Discipline; Disease; Dose; Drug Combinations; Drug Delivery Systems; Drug Kinetics; Drug resistance; Drug usage; Ensure; Evaluation; Excision; Fatigue; Formulation; Foundations; Frequencies; Funding; Future; Generations; HIV; HIV Infections; HIV therapy; Health; Human; Implant; In Vitro; Individual; Industrialization; Industry; Injectable; Injections; 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 silico; in vivo; in vivo evaluation; innovation; insight; interest; lead candidate; mathematical model; meetings; monomer; multiple drug use; nano; nanomedicine; nanoparticle; nanoparticle drug; non-nucleoside reverse transcriptase inhibitors; novel; novel therapeutics; patient advocacy group; pharmacokinetic model; pill; preclinical evaluation; predictive modeling; programs; safety assessment; 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HIV制剂需要终身每日给药，并且在长时间之后， 患者可能会出现药丸疲劳，并经常错过药物剂量。这可能会对 影响治疗的成功，增加病毒对药物产生耐药性的可能性 采用最近，领先的制药公司的创新已经证明了长期的潜力， 使药物能够每月仅给药一次（或甚至更少频率）， 在此期间持续输送药物。尽管这有可能极大地影响给药频率， 这种方法的主要局限性是需要同时使用 不同的药物，只有两种药物已开发出长效制剂。这意味着 患者必须每天口服一种叫做核苷逆转录酶的药物 抑制剂（NRTI）。两种工业长效治疗候选药物（利匹韦林LA和卡替拉韦LA） 使用研磨工艺制造，该工艺从水溶性差的 毒品NRTI具有固有的水溶性，因此目前与现有技术不相容。 被制药公司用来生产长效制剂。利用我们最近在 聚合物化学，前药化学，药理学和预测建模，我们建议产生和 优化由NRTI组成的长效骨干方案，以符合当前的护理标准， 最近的工业发展。一系列的四个NRTI将进行研究，我们将评估两个 管理选项，将建立长效NRTI交付的实用程序并定义新平台 许多水溶性药物的技术。中涉及的不同学科之间的迭代 协作计划将确保开发出货架稳定的临床相关选项，并发布 NRTI至少一个月。将通过早期安全性评价降低翻译风险。的 此外，还将确定所产生的每一个候选方案的稳健性、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，每个候选人都将接受连续和详细的临床前评估 它们的药理学和安全性，以优化有利的性质。主要候选人将是 通过数学建模整合实验室数据选择用于体内分析。我们的战略将 开发长效NRTI候选药物，并产生概念验证，以支持未来的工作，并吸引 第三方利益。影响将来自于一个新的平台，用于长效释放和患者获益 通过简化治疗和给药频率。

项目成果

Polymer-prodrug conjugates as candidates for degradable, long-acting implants, releasing the water-soluble nucleoside reverse-transcriptase inhibitor emtricitabine.

• DOI: 10.1039/d3tb02268d
• 发表时间: 2023-12-13
• 期刊: Journal of materials chemistry. B

Linear and branched polymer prodrugs of the water-soluble nucleoside reverse-transcriptase inhibitor emtricitabine as structural materials for long-acting implants.

• DOI: 10.1039/d2tb00825d
• 发表时间: 2022-06-15
• 期刊: Journal of materials chemistry. B