Assessing antiretroviral exposure in diverse populations

评估不同人群的抗逆转录病毒暴露情况

• 批准号: 7002541
• 负责人: Monica Gandhi
• 金额: $ 12.17万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7002541
• 关键词: HIV infections; age difference; antiAIDS agent; clinical research; dosage; epidemiology; gender difference; human subject; outcomes research; patient oriented research; pharmacokinetics; racial /ethnic difference

DESCRIPTION (provided by applicant): Despite the success of highly active antiretroviral therapy (HAART) on the population level, as many as 30-70% of patients in the clinical setting fail to achieve sustained virologic responses to HAART and toxicities are common. Treatment outcomes of HAART have many determinants, including the amount of drug that reaches the site of antiviral activity (exposure). Our ability to accurately measure exposure to antiretrovirals (ARVs) is currently limited, most notably secondary to the significant interindividual pharmacokinetic (PK) variability observed for these agents. Traditional methods of therapeutic drug monitoring employ single untimed blood levels of ARVs to assess exposure, which can't account for this interindividual PK variability; hence, these methods have had inconsistent success in predicting treatment responses and have not become routine measures in the clinical setting. Full PK studies for ARVs to date have been generally performed in highly selected patients (typically male) in order to minimize factors that may contribute to PK variability, thus limiting the generalizability of these results to typical patients in clinical care. I propose to employ a relatively novel methodology - population PK modeling - to identify sources of interindividual and intraindividual PK variability for ARVs and to calculate accurate ARV exposure measurements for diverse populations. In a prospective cohort of HIV-infected patients, I propose to quantify the factors that produce interindividual variability in ARV exposure using population PK methods with intensive PK sampling data obtained from a representative sample of HIV-infected women (Aim 1); to test whether ARV exposure estimates derived from sparse sampling, combined with individual covariate data, population models, and appropriate statistical methodologies, predict treatment outcomes more accurately than single plasma ARV levels (Aim 2), and to determine whether biologic sex influences PK variability for ARVs (Aim 3). My mentoring committee consists of internationally recognized scientists whose expertise spans pharmacology (Dr. Benet), epidemiology and observational research (Dr. Greenblatt), and biostatistics (Dr. Bacchetti). Their mentorship, as well as a focused training and research plan facilitated by a K23 award, will enable me to become an independent clinical investigator, focusing on the association of antiretroviral treatment exposure with responses to therapy in diverse populations.

描述（由申请人提供）：尽管在人群水平上取得了高度活跃的抗逆转录病毒疗法（HAART），但在临床环境中，多达30-70％的患者无法实现对HAART和毒性的持续病毒反应。 HAART的治疗结果有许多决定因素，包括达到抗病毒活性部位的药物量（暴露）。我们目前有限的准确测量暴露于抗逆转录病毒（ARV）的能力受到限制，最重要的是继发于这些药物观察到的显着个体间药代动力学（PK）变异性。传统的治疗药物监测方法采用单一未定的血液水平来评估暴露，这无法解释这种个体间的PK变异性；因此，这些方法在预测治疗反应方面取得了不一致的成功，并且在临床环境中尚未成为常规措施。迄今为止，对ARV的全面PK研究通常已经在高度选择的患者（通常是男性）中进行，以最大程度地减少可能导致PK变异性的因素，从而限制了这些结果对典型患者的临床护理中的概括性。 我建议采用一种相对新颖的方法 - 种群PK建模 - 以确定对ARV的个体间和个体内的PK变异性来源，并计算各种人群的准确ARV暴露测量。在预期的HIV感染患者中，我建议使用种群PK方法量化ARV暴露的个体变异性的因素，并具有从HIV感染的女性的代表性样本中获得的密集PK采样数据（AIM 1）；测试ARV暴露于稀疏采样中得出的估计，与单个协方差数据，人群模型和适当的统计方法结合使用，比单个血浆ARV水平更准确地预测治疗结果（AIM 2），并确定生物学性别是否影响PK的PK变异性（AIM 3）。我的指导委员会由国际认可的科学家组成，他们的专业知识涵盖了药理学（Benet博士），流行病学和观察性研究（Greenblatt博士）和生物统计学（Bacchetti博士）。他们的指导以及由K23奖项促进的重点培训和研究计划，使我能够成为独立的临床研究者，重点是抗逆转录病毒治疗暴露的关联，以及对不同人群中治疗的反应。