Clinical Study to Measure Pharmacokinetics, Pharmacodynamics and Safety of a TDF

测量 TDF 的药代动力学、药效学和安全性的临床研究

• 批准号: 8210597
• 负责人: MARLA J KELLER
• 金额: $ 46.11万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-10 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8210597
• 关键词: Adherence; Adverse event; Anti-Inflammatory Agents; Anti-Retroviral Agents; Anti-inflammatory; Antiviral Agents; Bacteria; Biological Assay; Biological Availability; Biological Response Modifiers; Cells; Clinical Research; Coitus; Communities; Data; Development; Diphosphates; Dose; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Environment; Epithelial; Epithelium; Female; Fluorescent in Situ Hybridization; Gel; Genital system; Goals; HIV; HIV-1; Human; Human Herpesvirus 2; Immune; In Vitro; Inflammatory; Kinetics; Lead; Life Cycle Stages; Local Microbicides; Measures; Microbial Biofilms; Molecular; Mucosal Immunity; Mucous Membrane; Oral; Outcome; Pathway interactions; Pelvic Examination; Permeability; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; Phase I Clinical Trials; Placebos; Plasma; Polyurethanes; Population; Preclinical Testing; Predisposition; Prodrugs; Production; Research Design; Reverse Transcriptase Inhibitors; Safety; Science; Sexual Transmission; Simplexvirus; Surface; Surrogate Markers; Symptoms; System; Tenofovir; Tenofovir disoproxil fumarate; Testing; Therapeutic; Tissues; Vagina; Vaginal Ring; Viral; Virus; Woman; Work; base; cost; design; human study; improved; inhibitor/antagonist; microbicide; novel; particle; phase 1 study; pre-clinical; prevent; primary outcome; programs; prototype; rRNA Genes; social; tool; uptake

The ultimate goal of this Program is to develop an intravaginal ring (IVR) for sustained delivery of a combination microbicide that will be safe and effective in preventing the sexual transmission of human immunodeficiency virus (HIV) and herpes simplex virus (HSV). A safe and effective microbicide will likely require sustained, local delivery of a combination of antiretroviral drugs that target different steps in the HIV life cycle and a delivery system that overcomes the challenges related to adherence. This will be accomplished through IVR formulation of the reverse transcriptase inhibitor, tenofovir disoproxil fumarate (TDF), combined with the entry inhibitor, maraviroc (MVC). The rationale for pursuing this combination is based on the recent promising results of CAPRISA 004 in which significant protection against HIV-1 and HSV-2 was observed with 1% TFV gel. Ongoing work in Projects 1 and 2 demonstrate potential advantages of a TDF compared to a TFV IVR, including more potent activity against HIV and HSV, greater tissue permeability, and the successful development of a polyurethane (PU) IVR formulation of TDF. An exploratory pre-Phase I study is proposed in this new Project to rigorously measure the pharmacokinetics (PK), pharmacodynamics (PD) and safety of TDF following ring delivery in healthy women. The primary outcomes to be measured are PK of TDF release into the genital tract and adverse events. PD will be evaluated by measuring the antiviral activity (HIV and HSV) in genital tract secretions (luminal) and tissue following IVR delivery of TDF. Ectocervical tissue will be challenged ex vivo with virus to assess drug bioavailability and activity. The impact of PU IVRs on the mucosal immune environment will be assessed by quantifying immune cell populations in the genital tract and concentrations of inflammatory, anti-inflammatory and soluble mucosal immune mediators in genital tract secretions. Advanced molecular microbiological tools will be employed including broad range 16S rRNA gene PCR with pyrosequencing to define the bacterial communities, and fluorescence in situ hybridization to determine if rings alter the epithelium and lead to vaginal biofilm formation. Results will inform the design of a Phase I trial of a TDF-MVC combination IVR.

该计划的最终目标是开发一种阴道环（IVR），用于持续提供一种复合杀微生物剂，这种杀微生物剂将安全有效地预防人类免疫缺陷病毒（HIV）和单纯疱疹病毒（HSV）的性传播。一种安全有效的杀微生物剂可能需要持续地在当地提供针对艾滋病毒生命周期不同阶段的抗逆转录病毒药物组合，以及克服与坚持使用有关的挑战的提供系统。这将通过逆转录酶抑制剂富马酸替诺福韦酯（TDF）与进入抑制剂马拉韦罗（MVC）的IVR制剂来实现。追求这种组合的基本原理是基于CAPRISA 004最近的有希望的结果，其中观察到1% TFV凝胶对HIV-1和HSV-2具有显著的保护作用。项目1和2中正在进行的工作证明了TDF与TFV IVR相比的潜在优势，包括更有效的抗HIV和HSV活性、更大的组织渗透性以及成功开发了TDF的聚氨酯（PU）IVR制剂。该新项目提出了一项探索性I期前研究，以严格测量健康女性环分娩后TDF的药代动力学（PK）、药效学（PD）和安全性。要测量的主要结果是TDF释放到生殖道中的PK和不良事件。将通过测量生殖道分泌物（管腔）和组织中的抗病毒活性（HIV和HSV）评价PD 在IVR传送TDF之后。将用病毒离体挑战外宫颈组织，以评估药物生物利用度和活性。将通过定量生殖道中的免疫细胞群以及生殖道分泌物中炎症、抗炎和可溶性粘膜免疫介质的浓度来评估PU IVR对粘膜免疫环境的影响。将采用先进的分子微生物学工具，包括广泛的16 S rRNA基因PCR与焦磷酸测序，以确定细菌群落，和荧光原位杂交，以确定环是否改变上皮细胞，并导致 阴道生物膜形成。结果将为TDF-MVC组合IVR的I期试验设计提供信息。