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

描述（由申请人提供）：Julie B. Dumond, PharmD， BCPS， AAHIVE， UNC Eshelman药学院药物治疗和实验治疗学部门的研究助理教授，是一名药剂师，在以患者为导向的研究方法方面受过良好的培训和背景，并已证明致力于应用这些方法来改善艾滋病毒感染者的抗逆转录病毒（ARV）使用。候选人的长期职业目标是成为一名独立资助的学术药理学家，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和多样化的经验。特别是，候选人将从事前瞻性人群药代动力学/药效学（PK/PD）数据收集，目的是量化影响药物反应和毒性的年龄相关因素。该职业发展奖项培养的候选人的短期职业目标是：1)获得高级PK/PD，生物统计学和计算方法的正式培训；2)获得人口PK/PD建模的实践经验；3)与领先的药物计量学家建立工作关系；4)为R34/U01或R01应用程序开发初步数据；5)扩大她在负责任的研究培训方面的培训。建议的研究计划，职业发展活动和指导团队都是唯一适合帮助申请人实现这些目标。该研究计划是围绕以下中心假设建立的：1)ARV药代动力学的改变会导致临床反应和毒性测量的药效学改变；2)实足年龄可能只能部分解释药代动力学的改变，以及随后的药效学改变。在本提案中，我们将针对两种常见的ARV方案，恩曲西他滨/替诺福韦/依非韦伦（Atripla）和恩曲西他滨/替诺福韦/阿扎那韦/利托那韦（Truvada， Reyataz和Norvir），建立一个药代动力学和药代动力学/药效学模型。为了实现这些目标，我们将使用最佳样本设计模拟来前瞻性地收集接受感兴趣方案的hiv感染成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等领域进行高级课程和独立研究，并进行动手建模培训。指导小组包括国际公认的独立资助的研究人员，他们在ARV临床药理学（Kashuba）、药物计量学（Forrest）和艾滋病毒临床护理和研究（Cohen）方面具有专业知识，他们将指导Dumond博士的研究、培训和专业发展。研究环境包括美国国立卫生研究院资助的转化和临床科学研究所和北卡罗来纳大学艾滋病研究中心以及纽约州立大学布法罗分校的药物科学系，将为追求上述研究和培训目标提供一个富有成效，学院和合作的氛围。

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.