Open-Labeled PK-PD Studies of Metoprolol ER

NCT02417246 | Completed Phase 4 Results DMC FDA Drug

• 3 other identifiers: IRB201500092FD14-024OCR15985
• Study Type: interventional
• Target: 61
• Locations: 1 country
• Sites: 2

Brief Summary

Recently, the quality of generic metoprolol extended-release (ER) products has been called into question with reports of inconsistent effects when switching from the brand name product to a generic formulation. Problems with how the body processes these drugs could have serious and widespread consequences given the high frequency of metoprolol ER use in the management of various cardiovascular disorders, including high blood pressure, coronary heart disease, heart failure, and cardiac arrhythmias. Investigators hypothesize that both product- and subject-specific factors lead to variability in the way the body breaks down the drug (pharmacokinetics) and clinical response to generic versus name brand metoprolol ER formulations. Investigators will study the brand name and generic metoprolol ER formulations in subjects with high blood pressure to compare the pharmacokinetics and cardiovascular responses among equivalent labeled doses of each product (brand name and two approved generics). The study objective is to provide information on how the body breaks down generic and brand name metoprolol ER products (pharmacokinetics) and how the body responds to generic and brand name metoprolol ER products (pharmacodynamics) to better understand if generic metoprolol ER products are as good as the brand name product.

Conditions

Blood Pressure

Keywords

pharmacokinetics; pharmacodynamics; pharmacogenetics

Outcome Measures

Primary Outcomes (2)

• Area Under the Plasma Concentration Versus Time Curve (AUC)

  The AUC of Brand name metoprolol ER will be compared against each generic for determination of bioequivalence. The mean and standard deviation (SD) values of AUC are entered separately for the 50mg, 100mg and 150mg doses. Results are reported for brand name metoprolol ER, Generic B and Generic A.

  0.0, 0.30, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 12.0, 16.0, 20.0, 24.0 hours post dose

• Peak Plasma Concentration (Cmax) of Metoprolol Succinate

  The Peak Plasma Concentration (Cmax) of Brand name metoprolol ER will be compared against each generic for determination of bioequivalence. The mean and SD values of Cmax are entered separately for the 50mg, 100mg and 150mg doses. Results are reported for brand name metoprolol ER, Generic B and Generic A.

  0.0, 0.30, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 12.0, 16.0, 20.0, 24.0 hours post dose

Secondary Outcomes (3)

• The Heart Rate Variability (HRV) Response to Brand Name Metoprolol ER Versus Each Generic Formulation of Metoprolol Succinate.

  Heart rate variability (Low-to-High Frequency Ratio) over each quartile of 6 hours in the 24-hr period

• Blood Pressure Values (Systolic and Diastolic) Compared Between Brand Name Metoprolol ER and Each Generic Metoprolol Formulation (Generic B, Generic A)

  Average value over each quartile of 6 hours in the 24-hr period

• Heart Rate (HR) Response Compared Between Brand Name Metoprolol ER and Each Generic (Generic B, Generic A) Formulation of Metoprolol Succinate

  Average value over each quartile of 6 hours in the 24-hr period

Study Arms (2)

Study Sequence A

ACTIVE COMPARATOR

Start with brand name metoprolol ER, switch to Generic B metoprolol, switch back to brand name metoprolol ER, then switch to Generic A metoprolol

Drug: brand name metoprolol ER; Drug: Generic A; Drug: Generic B

Study Sequence B

ACTIVE COMPARATOR

Start with brand name metoprolol ER, switch to Generic A metoprolol, switch back to brand name metoprolol ER, then switch to Generic B metoprolol.

Drug: brand name metoprolol ER; Drug: Generic A; Drug: Generic B

Interventions

brand name metoprolol ER DRUG

This medication will be taken for 7 to 28 days

Also known as: Metoprolol extended-release (ER)

Study Sequence A; Study Sequence B

Generic A DRUG

This medication will be taken for 7 days

Also known as: Metoprolol extended-release (ER)

Study Sequence A; Study Sequence B

Generic B DRUG

This medication will be taken for 7 days

Also known as: Metoprolol extended-release (ER)

Study Sequence A; Study Sequence B

Eligibility Criteria

• Age: 18 Years - 120 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects will be targeted for enrollment based on current treatment of their hypertension with a beta-blocker or known tolerability to a beta-blocker based on their previous participation in the Pharmacogenomic Evaluation of Antihypertensive Responses studies (PEAR-1 and PEAR-2). If necessary to meet enrollment targets, additional patients will be recruited from the existing patient population in the University of Florida Health Family Medicine clinic or through other means.

You may not qualify if:

• Documented secondary forms of hypertension
• Known cardiovascular disease (including history of angina pectoris, myocardial infarction, coronary revascularization procedure, heart failure, or presence of a cardiac pacemaker)
• Known cerebrovascular disease (including stroke and TIA)
• Known peripheral vascular disease
• Diabetes mellitus (Type 1 or 2) (defined as a diabetes diagnosis in the medical record or fasting blood glucose greater than or equal to 126 mg per dl or nonfasting blood glucose greater than or equal to 200 mg per dl on screening laboratories)
• Systolic blood pressure (SBP) greater than180 mm Hg on screening visit
• Heart rate less than 55 bpm on screening visit (in the absence of treatment with a beta-blocker)
• Renal insufficiency (serum creatinine greater than 1.5 in men or greater than 1.4 in women on screening laboratories)
• Liver enzymes (ALT and or AST) greater than 3 times the upper limit of normal on screening laboratories.
• Known Raynaud's phenomenon
• Known asthma or chronic obstructive pulmonary disease
• Pregnancy or lactation
• Gastric bezoar
• Swallowing disorders
• Strictures

Sponsors & Collaborators

• University of Florida: lead
• Food and Drug Administration (FDA): collaborator

Study Sites (2)

Family Medicine at Hampton Oaks Medical Plaza

Gainesville, Florida, 32607, United States

Location

Oak Hammock at the University of Florida

Gainesville, Florida, 32608, United States

Location

Limitations and Caveats

1. The final study sample size was lower than what was originally proposed based on power analysis. 2. The study protocol did not specify the attainment of steady-state prior to the 24-hour pharmacokinetic and pharmacodynamic studies.

Results Point of Contact

• Title: Dr. Larisa H Cavallari
• Organization: UF

lcavallari@cop.ufl.edu

352-273-8245

Study Officials

• Larisa Cavallari, PharmD

  University of Florida

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 1, 2015
• First Posted: April 15, 2015
• Study Start: August 1, 2015
• Primary Completion: June 6, 2018
• Study Completion: June 6, 2018
• Last Updated: February 10, 2020
• Results First Posted: November 8, 2019

Record last verified: 2020-02

Locations

US (2)