Long acting NRTI therapies for HIV

项目总结 目前可用的艾滋病毒制剂需要终生、每日剂量，并在延长时间后， 患者可能会出现服药疲劳，并经常错过服药剂量。这可能会产生有害的影响 影响治疗成功的后果，增加了病毒对药物产生抗药性的可能性 使用。最近，领先制药公司的创新已经展示了长期- 能够使药物每月只给药一次(或更少)的代理配方，但 在这段时间内维持药物的输送。尽管这有可能极大地影响给药频率， 这种方法的一个主要局限性是需要有效的治疗方法来同时使用 不同的药物，只有两种药物是用长效制剂开发的。这意味着 患者仍然必须每天服用一种名为核苷逆转录酶的药物的片剂。 抑制剂(NRTI)。两种工业长效候选药物(利培韦林LA和卡替格列韦LA) 使用研磨工艺制造，该工艺从难于溶于水的物质中产生固体药物纳米粒 毒品。NRTI具有固有的水溶性，因此目前与这些技术不兼容。 被制药公司用来生产长效配方。利用我们最新的进展 聚合物化学，前药物化学，药理学和预测模型，我们建议产生和 优化由NRTI组成的长效骨干方案，以匹配当前的护理标准和 称赞最近的工业发展。我们将研究一系列的四项NRTI，我们将评估两项 将为长效NRTI交付建立实用程序并定义新平台的管理选项 用于许多水溶性药物的技术。中涉及的不同规程之间的迭代 协作计划将确保开发与临床相关的选项，这些选项是货架稳定的，并可发布 在至少一个月的时间内进行国家技术援助。翻译将通过早期安全评估来降低风险。这个 生成的每个候选对象的健壮性、其可扩展性、无菌性和成本效益也将得到确立。 为了实现这一雄心勃勃的计划，每个候选人都将接受顺序和详细的临床前评估 对它们的药理和安全性进行研究，以优化其良好的特性。主要候选人将是 通过数学建模整合实验室数据，选择进行活体分析。我们的战略将 开发长效NRTI的候选人并生成概念验证以支持未来的工作和吸引 第三方利益。影响将来自一个新的平台，为患者提供长效释放和好处 通过简化治疗方法和给药频率。

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.