Optimizing Antiretroviral Use in Aging: Pharmacokinetics, Response, and Toxicity

优化抗逆转录病毒药物在衰老过程中的应用：药代动力学、反应和毒性

基本信息

批准号：
8814163
负责人：
Julie Brumer Dumond
金额：
$ 10.92万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8814163
关键词：
Acquired Immunodeficiency Syndrome Adult Adverse effects Affect Age Age-Years Aging Aging-Related Process Anti-Retroviral Agents Area Atazanavir Binding Proteins Biometry Buffaloes CDKN2A gene Cells Chronic Clinical Clinical Pharmacology Clinical Research Clinical Sciences Clinical Trials Computing Methodologies Data Data Collection Development Development Plans Diphosphates Disease Doctor of Pharmacy Dose Drug Kinetics Drug toxicity Elderly Environment Enzymes Evaluation Fostering Funding Future Gastric Acid Genetic Polymorphism Goals HIV Hepatic Mass Immune Immunologics Individual Institutes K-Series Research Career Programs Lead Life Life Expectancy Link Literature Measures Mentorship Methods Modeling New York North Carolina Patients Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Pharmacists Pharmacodynamics Pharmacologic Substance Pharmacotherapy Pharmacy Schools Phenotype Physiological Physiology Plasma Population Positioning Attribute Production Proteins Quality of life Recommendation Recruitment Activity Regimen Research Research Design Research Ethics Research Methodology Research Personnel Research Training Ritonavir Sampling Science Sex Behavior Surrogate Markers Tenofovir Therapeutic Toxic effect Training Translational Research United States United States National Institutes of Health Universities Work age related antiretroviral therapy career career development clinical care cohort design efavirenz emtricitabine experience frailty improved insight interest novel novel strategies older patient patient oriented research pharmacodynamic model pharmacokinetic model professional atmosphere professor prospective research and development response senescence simulation theories treatment response tripolyphosphate truvada

项目摘要

DESCRIPTION (provided by applicant): Julie B. Dumond, PharmD, BCPS, AAHIVE, Research Assistant Professor in the Division of Pharmacotherapy and Experimental Therapeutics at the UNC Eshelman School of Pharmacy, is a pharmacist with strong training and background in patient-oriented research methodology, and a proven commitment to applying these methods to improving antiretroviral (ARV) use in HIV-infected patients. The candidate's long-term-career goal is to be an independently funded, academic pharmacometrician, with a rich and diverse experience in pharmacokinetic/pharmacodynamic modeling of antiretroviral drugs. In particular, the candidate will pursue prospective population pharmacokinetic/pharmacodynamic (PK/PD) data collection, with the goal of quantifying age-related factors that influence drug response and toxicity. The candidate's short-term career goals fostered by this career development award are 1) to obtain formal training in advanced PK/PD, biostatistics, and computational methods, 2) to gain hands-on experience in population PK/PD modeling, 3) to foster working relationships with leading pharmacometricians, 4) to develop the preliminary data for an R34/U01 or R01 application, and 5) to expand her training in the responsible training of research. The proposed research plan, career development activities, and mentorship team are all uniquely suited to assist the applicant in achieving these goals. The research plan is built around the central hypothesis that: 1) altered ARV pharmacokinetics contributes to altered pharmacodynamics as measured by clinical response and toxicity, and 2) chronological age may only partly explain alterations in pharmacokinetics, and subsequently, pharmacodynamics. In this proposal, we will develop a pharmacokinetic and a pharmacokinetic/pharmacodynamic model in two specific aims for two common ARV regimens, emtricitabine/tenofovir/efavirenz (Atripla) and emtricitabine/tenofovir/atazanavir/ritonavir (Truvada, Reyataz, and Norvir). To accomplish these aims, we will use optimal sample design simulation to prospectively collect drug concentration and drug response data from HIV-infected adults receiving the regimens of interest. Subjects will be recruited from the University of North Carolina (UNC) Clinical HIV Cohort. To support the candidate's career development, she will pursue advanced coursework and independent study in the areas of pharmacokinetic and pharmacodynamic theory and modeling, biostatistics, computational methods, and research ethics, in concert with hands-on modeling training. The mentorship team, which includes internationally-recognized, independently-funded investigators with expertise in ARV clinical pharmacology (Kashuba), pharmacometrics (Forrest), and HIV clinical care and research (Cohen), will guide Dr. Dumond's research, training, and professional development. The research environment including the NIH-funded Translational and Clinical Sciences Institute and Center for AIDS Research at UNC and the Department of Pharmaceutical Sciences at the University at Buffalo, State University of New York, will provide a productive, collegial, and collaborative atmosphere in which to pursue the above research and training goals. NARRATIVE By 2015, more than 50% of the HIV-infected population in the United States will be at least 50 years of age, and little is known about the optimal clinical care of aging HIV-infected patients. The goal of this and subsequent research is to identify patient-specific factors modifying antiretroviral response and toxicity. This could lead to specific treatment recommendations for older HIV-infected patients.

描述（由申请人提供）：朱莉·B·杜蒙德（Julie B.候选人的长期职业目标是成为一名独立资助的学术药物学家，在抗逆转录病毒药物的药代动力学/药效学建模方面具有丰富而多样的经验。特别是，候选人将追求前瞻性人群药代动力学/药效学（PK/PD）数据收集，其目的是量化影响药物反应和毒性的年龄相关因素。该职业发展奖促进的候选人的短期职业目标是1）获得高级PK/PD的正式培训，生物统计学和计算方法，2）获得人口PK/PD模型的动手经验，3）促进与领先药物计的工作关系，与领先的药物计，4）为培训培训，以培训R34/U01或R01的培训，并进行5），并在5）进行了培训。拟议的研究计划，职业发展活动和指导团队都非常适合帮助申请人实现这些目标。该研究计划围绕以下中心假设构建：1）改变的ARV药代动力学改变了通过临床反应和毒性衡量的药效改变的改变，而2）年代年龄只能部分解释药代动力学的改变，随后是药物动力学的变化。在该提案中，我们将在两个特定目标中开发出一种药代动力学和药代动力学/药效学模型，用于两种常见的ARV方案，即Emtricitabine/Tenofovir/Efavirenz（Atripla）和Emtricyabine/tenofovir/tenofovir/tenofovir/tenofovir/tenazanavir/atazanavir/ritononavir/ritonavir（truvada，reyyataz和norvir）。为了实现这些目标，我们将使用最佳样品设计模拟来预期收集来自感兴趣方案的HIV感染成年人的药物浓度和药物反应数据。受试者将从北卡罗来纳大学（UNC）临床HIV队列中招募。为了支持候选人的职业发展，她将在药代动力学和药效学理论和建模，生物统计学，计算方法和研究伦理方面进行高级课程和独立研究，并与动手建模培训一起。包括国际认可的独立资助的研究人员，具有ARV临床药理学专业知识（Kashuba），药物计量学（Forrest）和HIV临床护理和研究（COHEN），该指导团队将指导杜蒙德博士的研究，培训，培训，专业发展和专业发展。包括NIH资助的转化和临床科学研究所以及UNC的艾滋病研究中心以及纽约州立大学布法罗大学的制药科学系在内的研究环境将提供一种富有成效的，合作和协作的氛围，以实现上述研究和培训目标。到2015年，美国超过50％的艾滋病毒感染人群至少将年满50岁，并且对感染HIV感染的HIV患者的最佳临床护理知之甚少。此目的和随后的研究的目的是确定改变抗逆转录病毒反应和毒性的患者特异性因素。这可能会导致对年龄较大的HIV感染患者的特定治疗建议。