FDA Pharmacokinetic and Pharmacodynamic (PK-PD) Studies Grant for Cardiovascular Drugs

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.