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

项目摘要 最近，美托洛尔缓释（ER）产品的质量受到质疑， 报告了在品牌名称和通用配方之间转换时的不一致效果。问题 考虑到美托洛尔ER的使用频率， 各种心血管疾病的管理，包括高血压、心力衰竭和缺血性心脏病 我们假设产品和患者特异性因素均导致药代动力学的变异性 和对不同美托洛尔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，以帮助FDA更好地了解哪些因素应该 在美托洛尔ER产品的生物等效性研究中考虑。我们将通过以下方式解决我们的假设： 具体目的如下：1）比较品牌名称的药动学和心血管效应， 普通美托洛尔ER产品在高血压患者中的应用; 2）确定胃pH变化的影响 不同美托洛尔ER产品的浓度-反应关系; 3）检查 CYP 2D 6基因型对不同美托洛尔ER产品药代动力学的影响这个提议很重要 因为它将有助于阐明导致药代动力学和有效性变化的因素， 美托洛尔ER产品，这是在美国最常用的处方药，这样的研究是 必须通过告知，确保安全和高质量的美托洛尔ER替代品的可用性 生物等效性指标和标准。拟议的研究是创新的，因为我们将使用各种 定义临床应答的方法，与定义CYP 2D 6的最新方法相结合 基因型和胃pH值和动力，这与我们在临床β受体阻滞剂试验方面的丰富经验， 已发表的对映选择性美托洛尔测定、药物基因组学和创新的药物计量学建模 这些方法将产生高质量的数据，这些数据将能够清楚地解决以下问题： 各种美托洛尔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.