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 ?-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.

Public Health Relevance

Metoprolol succinate is widely used in the management of heart diseases and is available in generic formulations. However, recent reports suggest problems with generic metoprolol succinate, which could compromise the drug's safety and effectiveness. This University of Florida application will compare the pharmacokinetics and pharmacodynamics of brand name and generic metoprolol succinate formulations in patients with hypertension, taking into account gastric pH and genetic polymorphism, to identify product- and patient-specific factors that lead to variance in response to different metoprolol succinate formulations. Our goal through completion of this project is to help inform bioequivalence metrics for metoprolol succinate products to ensure availability of safe and high quality generic alternatives.

Agency
National Institute of Health (NIH)
Institute
Food and Drug Administration (FDA)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01FD005235-01
Application #
8858137
Study Section
Special Emphasis Panel (ZFD1-SRC (99))
Project Start
2014-09-10
Project End
2017-08-31
Budget Start
2014-09-10
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Florida
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611