Development of prodrug approaches for long-acting nanoformulations of emtricitabine-based regimens

开发基于恩曲他滨的方案的长效纳米制剂的前药方法

• 批准号: 9410823
• 负责人: Amer Al-khouja
• 金额: $ 4.4万
• 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: 2017-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9410823
• 关键词: AIDS prevention; Adherence; Ally; Amides; Anti-Retroviral Agents; Antiviral Agents; Ants; Biological Models; Carbamates; Cells; Collaborations; Combined Modality Therapy; Computer Simulation; Development; Dose; Drug Kinetics; Emulsions; Evaluation; Fatigue; Formulation; Freezing; Generations; Goals; HIV; Human; Hydrophobicity; Hydroxyl Radical; ImProv; In Vitro; Infection; Infection prevention; Integrase Inhibitors; Intramuscular; Intramuscular Injections; Ions; Kinetics; Laboratories; Lead; Liquid substance; Masks; Measures; Metabolic Activation; Patients; Pharmaceutical Preparations; Physiological; Prevention; Prodrugs; Production; Regimen; Reporting; Research; Reverse Transcriptase Inhibitors; Risk; Series; Side; Solid; Solubility; Technology; Testing; Time; Transcriptase; Treatment Efficacy; Treatment Failure; Universities; Ursidae Family; Water; Work; analog; base; compliance behavior; design; emtricitabine; esterase; hydrophilicity; improved; in vivo Model; inhibitor/antagonist; lipophilicity; mortality; nanoformulation; nanoparticle; non-nucleoside reverse transcriptase inhibitors; pharmacokinetic model; pill; success; water solubility

Project Summary Current antiretroviral (ARV) medications for HIV treatment and prevention require lifelong daily dosing, which can lead to reduced patient adherence due to pill fatigue, increasing the likelihood for treatment failure. Long-acting (LA) ARVs would allow less frequent administration, improving adherence. Despite success in the development of LA formulations for the non-nucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine and the integrase inhibitor cabotegravir, the nanomilling technologies used to produce them are incompatible with the nucleos(t)ide reverse transcriptase inhibitors (NRTIs) due to their high water solubility. Most current ARV combination therapies include administration of the NRTIs. Thus, in order to produce a complete LA dosing regimen, LA formulations of NRTIs are required. To enable the production of hydrophobic solid drug nanoparticles (SDNs), we propose the design, synthesis, and evaluation of a series of tunable emtricitabine (FTC) prodrugs that mask key hydrophilic groups and make these drugs compatible with SDN formulation approaches. Prodrug activation kinetics will be measured under a variety of physiologically relevant conditions to mimic those encountered by the complete regimen administered via intramuscular depot. In addition, prodrugs will be analyzed for lipophilicity and antiviral activity in cases where it is likely prodrugs will reach and undergo activation in target cells. The most promising candidates will be used to generate SDNs. The pharmacokinetic and efficacy benefits of these formulations will be tested with in vitro and in vivo model systems, guided by in silico physiologically-based pharmacokinetic modeling in collaboration with the University of Liverpool. Overall, this research is expected to accelerate the development of complete LA-ARV regimens to significantly improve adherence.

项目摘要 目前用于艾滋病毒治疗和预防的抗逆转录病毒（ARV）药物需要终身每日服用 给药，这可能会导致减少患者的依从性，由于药丸疲劳，增加的可能性 治疗失败。长效抗逆转录病毒药物（LA）可以减少给药频率， 坚持。尽管成功开发了用于非核苷类药物的LA制剂， 逆转录酶抑制剂（NNRTI）利匹韦林和整合酶抑制剂卡替拉韦， 用于生产它们的纳米研磨技术与核（酸）ide反转不相容 转录酶抑制剂（NRTI），由于其高水溶性。目前最流行的抗逆转录病毒药物组合 治疗包括施用NRTI。因此，为了产生完整的LA给药， 方案，需要NRTI的LA制剂。为了能够生产疏水固体， 药物纳米颗粒（SDNs），我们提出了一系列的设计，合成和评估， 可调的恩曲他滨（FTC）前药，其掩蔽关键亲水基团并使这些药物 与SDN公式化方法兼容。将测量前药活化动力学 在各种生理学相关条件下，以模拟 通过肌内贮库给药的完整方案。此外，将分析前药 对于亲脂性和抗病毒活性，在前药可能到达并经历 在靶细胞中激活。最有希望的候选者将用于生成SDN。的 这些制剂的药代动力学和功效益处将在体外和体内进行测试。 体内模型系统，由基于计算机生理学的药代动力学建模指导， 与利物浦大学合作。总的来说，这项研究有望加速 开发完整的LA-ARV方案，以显著提高依从性。