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

• 批准号: 8429489
• 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
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8429489
• 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; planetary Atmosphere; professor; prospective; research and development; response; senescence; simulation; theories; treatment response; tripolyphosphate; truvada

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）：Julie B. Dumond，药学博士，BCPS，AAHIVE，北卡罗来纳大学埃谢尔曼药学院药物治疗和实验治疗学部研究助理教授，是一名药剂师，在以患者为导向的研究方法方面拥有丰富的培训和背景，并致力于应用这些方法来改善 HIV 感染患者的抗逆转录病毒 (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/药效学建模方面拥有丰富多样的经验。特别是，候选人将追求前瞻性群体药代动力学/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。该职业发展奖培育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方面的正式培训，2) 获得群体 PK/PD 建模的实践经验，3) 培养与领先药理学家的工作关系，4) 为 R34/U01 或 R01 应用开发初步数据，5) 扩大她在负责任的研究培训方面的培训。拟议的研究计划、职业发展活动和导师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建立：1）抗逆转录病毒药代动力学的改变导致通过临床反应和毒性测量的药效学改变；2）实际年龄可能只能部分解释药代动力学的改变，以及随后的药效学的改变。在本提案中，我们将为两种常见的 ARV 治疗方案（恩曲他滨/替诺福韦/依非韦伦（Atripla）和恩曲他滨/替诺福韦/阿扎那韦/利托那韦（Truvada、Reyataz 和 Norvir））开发两个特定目标的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治疗方案的 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理论与建模、生物统计学、计算方法和研究伦理学领域进行高级课程和独立研究，并结合实践建模培训。导师团队包括国际公认的、独立资助的研究人员，他们在抗逆转录病毒临床药理学 (Kashuba)、药理学 (Forrest) 和艾滋病毒临床护理和研究 (Cohen) 方面具有专业知识，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北卡罗来纳大学转化与临床科学研究所和艾滋病研究中心以及纽约州立大学布法罗大学药学系，将为实现上述研究和培训目标提供富有成效、学院和协作的氛围。 叙述 到 2015 年，美国超过 50% 的 HIV 感染者年龄将超过 50 岁，而人们对老年 HIV 感染者的最佳临床护理知之甚少。这项研究和后续研究的目标是确定改变抗逆转录病毒反应和毒性的患者特异性因素。这可能会为老年艾滋病毒感染者提出具体的治疗建议。