Long Acting Film Technology for Contraception and HIV Prevention (LATCH)

用于避孕和艾滋病毒预防的长效薄膜技术 (LATCH)

• 批准号: 10545302
• 负责人: Lisa Cencia Rohan
• 金额: $ 102.71万
• 依托单位: MAGEE-WOMEN'S RES INST AND FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-19 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10545302
• 关键词: 2' -deoxyadenosine; AIDS prevention; Achievement; Adherence; Anti-HIV Agents; Antiviral Agents; Area; Atopobium vaginae; Biological Availability; Cervical; Coitus; Contraceptive Agents; Contraceptive methods; Data; Development; Dosage Forms; Dose; Drug Combinations; Drug Delivery Systems; Drug Interactions; Drug Kinetics; Epithelial; Etonogestrel; Female; Film; Formulation; Generations; Glycoproteins; Goals; HIV; HIV Infections; HIV drug resistance; HIV therapy; High Risk Woman; In Vitro; Infection; Intravaginal Administration; Knowledge; Lead; Levonorgestrel; Macaca; Machine Learning; Mammalian Oviducts; Mediating; Menstruation; Metabolism; Methods; Modeling; Monitor; Nucleosides; Oryctolagus cuniculus; Parents; Permeability; Pharmaceutical Preparations; Phase; Pregnancy; Prevention; Prodrugs; Progestins; Rattus; Resistance profile; Reverse Transcriptase Inhibitors; SIV; Safety; Sex Behavior; Technology; Tissues; Toxic effect; Vagina; Vendor; Woman; Work; base; condoms; contraceptive efficacy; cost; design; drug release profile; efficacy testing; experience; experimental study; improved; in vivo; manufacturing scale-up; metabolic abnormality assessment; microbiota; next generation; nonhuman primate; novel; phase 1 study; physical property; prevent; protective factors; prototype; reproductive tract; research clinical testing; safety and feasibility; safety testing; simian human immunodeficiency virus; success; unintended pregnancy; vaginal microbiota

PROJECT ABSTRACT Several studies (ASPIRE, VOICE) have shown that adherence is paramount to the success of HIV prevention methods in women. Providing women with options through alternative drug delivery technologies can positively impact adherence. A compelling strategy includes co-delivery of an anti-HIV agent with a contraceptive agent to prevent pregnancy. This proposal plans to develop a next generation multipurpose prevention technology (MPT) film platform for once a month intravaginal administration of the 4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) prodrug (EFdA-P) and a progestin (levonorgestrel (LNG) or etonogestrel (ENG)) to achieve the dual goal of preventing HIV infection and pregnancy. EFdA-P showed increased bioavailability and tissue permeability compared to the parent EFdA, a highly potent exciting new antiviral drug. This versatile extended release MPT film platform is intended to provide a discrete, low cost and convenient alternative to women at high risk of HIV infection and unintended pregnancy. Recent data from our lab shows that films can deliver an anti-HIV agent in the vagina for up to 1 month even in the context of menses and sexual intercourse. Using this knowledge and our expertise in the development of intravaginal films, this proposal will develop a film platform for co-delivery of a progestin (licensed contraceptive agent) and EFdA-P at a predetermined rate for at least 1 month. MPT films containing EFdA will also be generated for comparison. The R61 phase of this milestone driven proposal will generate critical preformulation data for EFdA/EFdA-P and LNG/ENG drug combinations and optimize the MPT film formulation to achieve one- month delivery of both drugs with desired short-term stability. This phase will also establish the compatibility of film prototype with vaginal tissue and microbial flora in vitro followed by vaginal retention studies in the non- human primate (NHP) model. The R61 phase will demonstrate the ability of the MPT film prototype to attain desired release profiles of both drugs in vivo (NHP model). Using a clearly defined go / no go criteria, a lead MPT film will be transitioned to the R33 phase. The R33 phase will involve IND-enabling activities including drug- drug interaction, in vitro transporter and metabolism studies, manufacturing scale up and establishing long-term stability of the lead MPT film. It will also demonstrate the safety (rat, rabbit, and NHP) and efficacy of the lead MPT film against SHIV infection in NHP model. It will also confirm the ability of the film to function in the context of sexual activity and its ability to deliver contraceptive levels of progestin in the NHP model. The successful completion of proposed work will generate a novel extended release MPT film platform that can be applied to other drug combinations.

项目摘要 多项研究（ASPIRE、VOICE）表明，坚持对于艾滋病毒预防的成功至关重要 女性的方法。通过替代药物输送技术为妇女提供选择可以积极地 影响依从性。一项令人信服的策略包括同时施用抗 HIV 药物和避孕药物，以 预防怀孕。该提案计划开发下一代多用途预防技术（MPT） 每月一次阴道内施用 4'-乙炔基-2-氟-2'-脱氧腺苷 (EFdA) 的薄膜平台 前药（EFdA-P）和孕激素（左炔诺孕酮（LNG）或依托孕烯（ENG））以实现双重目标 预防艾滋病毒感染和怀孕。 EFdA-P 显示出增加的生物利用度和组织渗透性 与母体 EFdA 相比，EFdA 是一种高效、令人兴奋的新型抗病毒药物。这种多功能缓释 MPT 电影平台旨在为艾滋病毒高危女性提供一种独立、低成本且方便的替代方案 感染和意外怀孕。 我们实验室的最新数据表明，薄膜可以在阴道内提供抗 HIV 药物长达 1 个月，即使在 月经和性交的背景。利用这些知识和我们的专业知识来开发 阴道内薄膜，该提案将开发一个薄膜平台，用于共同输送孕激素（许可的避孕药） 剂）和 EFdA-P 以预定的速率持续至少 1 个月。含有 EFdA 的 MPT 薄膜也将 生成用于比较。这一里程碑驱动提案的 R61 阶段将产生关键的预配方 EFdA/EFdA-P 和 LNG/ENG 药物组合的数据并优化 MPT 薄膜配方以实现一 两种药物的月交付具有所需的短期稳定性。此阶段还将建立兼容性 体外阴道组织和微生物菌群的胶片原型，然后在非阴道中进行保留研究 人类灵长类动物（NHP）模型。 R61 阶段将展示 MPT 薄膜原型实现 两种药物体内所需的释放曲线（NHP 模型）。使用明确定义的通过/不通过标准，领先 MPT薄膜将过渡到R33相。 R33阶段将涉及IND支持活动，包括药物- 药物相互作用、体外转运蛋白和代谢研究、生产规模扩大和建立长期 铅MPT薄膜的稳定性。它还将证明先导药物的安全性（大鼠、兔子和 NHP）和功效 NHP 模型中针对 SHIV 感染的 MPT 膜。它还将确认电影在上下文中发挥作用的能力 NHP 模型中性活动的影响及其提供孕激素避孕水平的能力。成功者 完成拟议的工作将产生一个新颖的缓释 MPT 薄膜平台，可应用于 其他药物组合。