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

心血管药物的药代动力学和药效学（PK-PD）研究（U01）

• 批准号: 8858137
• 负责人: Larisa Humma Cavallari
• 金额: $ 62.23万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-10 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8858137
• 关键词: Pharmacokinetic; Pharmacodynamic; PK; PD; Studies

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.

项目概要 最近，美托洛尔仿制药缓释 (ER) 产品的质量受到质疑 有报告称在品牌名称和通用配方之间切换时效果不一致。 鉴于美托洛尔缓释剂在以下领域的使用频率，生物等效性可能会产生严重而广泛的后果： 治疗各种心血管疾病，包括高血压、心力衰竭和缺血性心脏 我们发现产品和患者特定因素都会导致药代动力学的变异 以及对不同美托洛尔缓释制剂的临床反应 该项目的目标是提供。 药代动力学和药效学数据可帮助 FDA 更好地了解应考虑哪些因素 我们将在美托洛尔缓释产品的生物等效性研究中考虑这一点。 具体目标如下：1）比较品牌和药物的药代动力学和心血管作用 普通美托洛尔缓释产品对高血压患者的影响；2) 确定胃部 pH 值变化的影响 不同美托洛尔 ER 产品的反应-反应关系；以及 3 个浓度）检查效果 CYP2D6 基因型对不同美托洛尔缓释产品药代动力学的影响 该建议很重要。 因为它将有助于阐明导致药代动力学和有效性变异的因素 美托洛尔缓释产品，是美国最常用的处方药之一。此类研究是 通过通知确保获得安全和高质量的通用美托洛尔缓释替代品至关重要 所提出的研究具有创新性，因为我们将使用多种方法。 定义临床反应的方法，与定义 CYP2D6 的最先进方法相结合 基因型、胃 pH 值和蠕动性，凭借我们在临床 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药理学模型 这些方法将产生高质量的数据，能够清楚地解决有关问题 各种美托洛尔缓释产品的生物等效性。