Pharmacokinetic and Pharmacodynamic (PK-PD) Studies of Cardiovascular Drugs (U01)

项目摘要 最近，非专利美托洛尔缓释(ER)产品的质量受到了质疑 在品牌名称和仿制药之间切换时产生不一致影响的报告。存在以下问题 鉴于美托洛尔ER在体内的使用频率，生物等效性可能会产生严重和广泛的后果 各种心血管疾病的处理，包括高血压、心力衰竭和缺血性心脏 疾病。我们假设产品和患者的特定因素都会导致药代动力学的变异性。 以及对不同美托洛尔ER制剂的临床反应。该项目的目标是提供 药代动力学和药效学数据，帮助FDA更好地理解哪些因素应该 在美托洛尔ER产品的生物等效性研究中考虑。我们将用我们的假设 Followingspecificaims:1)comparethepharmacokineticsandcardiovasculareffectsofbrandnameand 非专利美托洛尔ER产品在高血压患者中的应用；2)确定胃pH值变化的影响 美托洛尔ER不同产品的量效关系；3)考察美托洛尔对ER的影响 CYP2D6基因对不同美托洛尔ER产品药代动力学的影响这项建议很重要 因为这将有助于阐明导致药物动力学和有效性变异的因素。 美托洛尔ER产品是美国最常用的处方药之一。 对于确保安全和高质量的非专利美托洛尔ER替代品的可用性至关重要 生物等效性指标和标准。拟议的研究具有创新性，因为我们将使用各种 定义临床反应的方法，与定义CYP2D6的最新方法相结合 以我们在β阻滞剂临床试验中的丰富经验， 已发表的对映体选择性美托洛尔分析、药物基因组学和创新的药物计量模型 方法将产生高质量的数据，能够清楚地解决以下问题 不同美托洛尔ER产品的生物等效性。

Project Summary Recently, the quality of generic metoprolol extended-release (ER) products has been called into question with reports of inconsistent effects when switching between brand name and generic formulations. Problems with bioequivalence could have serious and widespread consequences given the frequency of metoprolol ER use in the management of various cardiovascular disorders, including hypertension, heart failure, and ischemic heart disease.We hypothesize that both product- and patient-specific factors lead to variability in pharmacokinetics and clinical responses to different metoprolol ER formulations. The goal of this project is to provide pharmacokinetic and pharmacodynamic data to help the FDA better understand which factors should be considered in bioequivalence studies of metoprolol ER products. We will address our hypotheses with the followingspecificaims:1)comparethepharmacokineticsandcardiovasculareffectsofbrandnameand generic metoprolol ER products in patients with hypertension; 2) determine the impact of gastric pH variation on the concentration-response relationship with different metoprolol ER products; and 3) examine the effect of CYP2D6 genotype on the pharmacokinetics of different metoprolol ER products. This proposal is important because it will help elucidate factors contributing to variability in the pharmacokinetics and effectiveness of metoprolol ER products, which are among the most commonly prescribed agents in the U.S. Such research is essential to ensure availability of safe and high quality generic metoprolol ER alternatives through informing bioequivalence metrics and criteria. The proposed studies are innovative in that we will use of a variety of approaches to define clinical response, integrated with state of the art approaches for defining CYP2D6 genotype and gastric pH and motility, which with our extensive experience with clinical β-blocker trials, published enantioselective metoprolol assays, pharmacogenomics, and innovative pharmacometric modeling approaches will lead to high quality data that will be able to clearly address the questions regarding bioequivalence of various metoprolol ER products.