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

基本信息

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
项目类别：
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

项目摘要

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个持续交付菌心的内部阴道环（IVR），这将是安全有效地防止人类免疫缺陷病毒（HIV）和单纯疱疹病毒（HSV）的性传播。安全有效的杀菌剂可能需要持续的局部输送抗逆转录病毒药物的组合，该药物针对艾滋病毒生命周期中的不同步骤和克服与依从性相关的挑战的输送系统。这将通过IVR制剂的逆转录酶抑制剂（Tenofovir disoprox fumarate（TDF））与入口抑制剂Maraviroc（MVC）结合来实现。追求这种组合的理由是基于CAPRISA 004的最新有希望的结果，在该结果中，使用1％TFV凝胶观察到对HIV-1和HSV-2的显着保护。与TFV IVR相比，项目1和2中的正在进行的工作表明了TDF的潜在优势，包括针对HIV和HSV的更有效的活性，更大的组织渗透性以及成功开发了TDF的聚氨酯（PU）IVR制剂。在健康妇女中，在这项新项目中提出了一项探索性的I研究研究，以严格测量药代动力学（PK），药效学（PD）和TDF的安全性。要测量的主要结果是将TDF释放到生殖道和不良事件中。 PD将通过测量生殖道分泌（Luminal）和组织中的抗病毒活性（HIV和HSV）来评估 IVR输送TDF之后。外部组织将受到病毒的离体挑战，以评估药物的生物利用度和活性。 PU IVR对粘膜免疫环境的影响将通过量化生殖道中的免疫细胞种群以及生殖道分泌物中的炎症，抗炎和可溶性粘膜免疫介质的浓度来评估。将采用晚期分子微生物工具，包括带有焦磷酸测序的宽范围16S rRNA基因PCR来定义细菌群落，并原位杂交荧光，以确定环是否改变了上皮并导致上皮阴道生物膜形成。结果将为TDF-MVC组合IVR的I期试验的设计提供信息。