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

Quick Facts

Due DateJune 2, 2014 (Monday)
Award Amount$ 750,000 - $ 1,000,000
Category of Funding ActivityHealth
Science and Technology and other Research and Development
Eligible Applicants
  • State governments
  • County governments
  • City or township governments
  • Special district governments
  • Independent school districts
  • Public and State controlled institutions of higher education
  • Native American tribal governments (Federally recognized)
  • Public housing authorities/Indian housing authorities
  • Native American tribal organizations (other than Federally recognized tribal governments)
  • Nonprofits having a 501 (c) (3) status with the IRS, other than institutions of higher education
  • Nonprofits that do not have a 501 (c) (3) status with the IRS, other than institutions of higher education
  • Private institutions of higher education
  • For-profit organizations other than small businesses
  • Small businesses
  • Others - Foreign Recipients

Program Description

Background: Metoprolol is a selective β1 receptor blocker used in treatment of several cardiovascular diseases, especially hypertension. Metoprolol is metabolized primarily by the cytochrome P450 isoform CYP2D6, which is subject to a genetic polymorphism. It has been formulated in different salt forms including tartrate, fumarate, and succinate salts, as well as different dosage forms such as immediate release and, extended release products. Different metoprolol drug products showed different pH-dependent drug release characteristics which seem to be consistent with the observed PK profile differences. The US FDA currently recommends single dose bioequivalence studies in healthy subjects to establish the bioequivalence of generic metoprolol products with their corresponding reference listed drug (RLD) based on 90% confidence interval of Cmax and AUC within 80.00-125.00%. The same bioequivalence criteria apply to any post approval changes of brand products which require in-vivo bioequivalence studies. Therapeutic inefficacy and adverse events have been reported by physicians and patients switching from brand to generic metoprolol extended release products. The FDA continues to monitor the FDA Adverse Event Reporting System (FAERS) for reports relating to currently marketed metoprolol products. However, based on current data available to the agency, it is difficult to draw definitive conclusions about the cause of the concern. Therefore, PK/PD studies in patient population are needed to help address the potential bioequivalence and therapeutic equivalence issues with metoprolol products. Objectives: The objectives of this project are to conduct a prospective PK/PD study in hypertensive patients to link the PK profiles to the time-course of PD activity of metoprolol, therefore, to identify the key product attributes and patient factors that may impact the therapeutic equivalence of metoprolol products. The specific objectives of the study were to: 1) Evaluate the PK-PD relationship; 2) Evaluate the effect of treatment (before and after switching metoprolol products) on the PK-PD relationship; 3) Evaluate the effect of pH variation in the population and rate of delivery on the PK-PD relationship; 4) Evaluate the effect of CYP2D6 phenotype on the PK-PD relationship; Detailed Description: Additional details regarding the study objectives are listed below: A prospective, randomized crossover trial design is suggested, i.e., switching over to a different metoprolol product at the same dose level as the prior one. The study should use a combination of products having different shapes of PK profiles. Simultaneous collections of PK and PD samples (before and after switch) at steady state are recommended to link PK profiles to PD effect. The selection of appropriate PD endpoint(s) has to be well justified. The study should enroll CYP2D6 extensive and poor metabolizers to assess the CYP2D6 phenotype impact on the PK profiles and PD activity of metoprolol extended release tablets. The study should evaluate the pH variations of the population and its impact on the PK profiles and PD effect of metoprolol extended release tablets. The focus of the first year is to develop a study protocol for FDA Research in Human Subject Committee (RIHSC) and investigator Institution Research Board (IRB) approval, product blinding, quality testing, bioanalytical method validation, and patient enrollment.

General Information

Funding Opportunity NumberRFA-FD-14-024
Funding Opportunity TitlePharmacokinetic and Pharmacodynamic (PK-PD) Studies of Cardiovascular Drugs (U01)
Opportunity CategoryHealth
Science and Technology and other Research and Development
Funding Instrument TypeCooperative Agreement
Category ExplanationNot Available
Number of Awards1
Cost Sharing or Matching RequirementNo
Posted DateApril 18, 2014 (Friday)
Application Due DateJune 2, 2014 (Monday)
Application Archive DateJuly 2, 2014 (Wednesday)
Total Program Funding$ 3,000,000
Award Amount$ 750,000 - $ 1,000,000
CFDA Number
  • 93.103 - Food and Drug Administration_Research

Eligible Applicants

  • State governments
  • County governments
  • City or township governments
  • Special district governments
  • Independent school districts
  • Public and State controlled institutions of higher education
  • Native American tribal governments (Federally recognized)
  • Public housing authorities/Indian housing authorities
  • Native American tribal organizations (other than Federally recognized tribal governments)
  • Nonprofits having a 501 (c) (3) status with the IRS, other than institutions of higher education
  • Nonprofits that do not have a 501 (c) (3) status with the IRS, other than institutions of higher education
  • Private institutions of higher education
  • For-profit organizations other than small businesses
  • Small businesses
  • Others - Foreign Recipients

Contact Information

Agency NameDepartment of Health and Human Services
Program Information WebsiteCopy of published RFA
ContactOffice: Food & Drug Administration
Gladys Melendez-Bohler
Grants Management Officer/Specialist
Phone 240-402-7565
FDA Office

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Application Due Date:
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