Open-Labeled PK-PD Studies of Metoprolol ER

Condition(s) targeted: Blood Pressure

Intervention: Toprol XL (Drug); SmartPill Capsule (Device); Exercise Treadmill (Procedure); 24 hour holter monitor (Procedure); 24-hour pharmacokinetic parameters (Other); Wockhardt metoprolol (Drug); Activas metoprolol (Drug)

Phase: Phase 4

Status: Not yet recruiting

Sponsored by: University of Florida

Official(s) and/or principal investigator(s):
Larisa Cavallari, PharmD, Principal Investigator, Affiliation: University of Florida

Overall contact:
Larisa Cavallari, PharmD, Phone: (352) 273-8245, Email: lcavallari@cop.ufl.edu

Recently, the quality of generic metoprolol extended-release (ER) (Toprol XL, Activas,Wockhardt) 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 formulation. 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. 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.

Official title: Open-Labeled Pharmacokinetic and Pharmacodynamic (PK-PD) Studies of Metoprolol ER

Study design: Allocation: Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Basic Science

Primary outcome:

Area under the plasma concentration versus time curve (AUC) of Toprol XL compared to Wockhardt metoprolol.

Area under the plasma concentration versus time curve (AUC) of Toprol XL compared to Activas metoprolol.

Peak Plasma Concentration (Cmax) of Toprol XL compared to Wockhardt metoprolol.

Peak Plasma Concentration (Cmax) of of Toprol XL compared to Activas metoprolol.

Secondary outcome:

Changes at day 14, day 49, and day 84 for 24-hour Holter monitor for heart rate between different drug formulations.

Changes at day 14, day 49, and day 84 in blood pressure between the different drug formulations.

Changes at day 14, day 49, and day 84 for exercise-induced heart rate.

Changes at day 14, day 49, and day 84 in gastrointestinal pH and proton pump inhibitors used.

CYP2D6 genotype on drug concentration

CYP2D6 genotype on the response to different drug formulations.

Detailed description: As a participant in this study the following will happen. A study nurse will draw 3 teaspoonfuls (15 ml) of blood. Two teaspoons (10ml) will be drawn for basic blood work and one teaspoon (5ml) will be drawn for genotyping. The study physician, Dr. Sigfried Schmidt will perform a physical exam and discuss all medical history. The study will be randomized to one of two groups like flipping a coin.

- Study Group A- start with Toprol XL, switch to Wockhardt metoprolol, switch back to

Toprol XL, then switch to Activas metoprolol

- Study Group B- start with Toprol XL, switch to Activas metoprolol, switch back to

Toprol XL, then switch to Wockhardt metoprolol. Each study group will consist of treatment with Toprol XL for 2 periods, treatment with Wockhardt metoprolol for one period, and treatment with Activas metoprolol for one period. The generic drug periods will be in a different order for each study group. During the times the switch will take place the following tests will be performed: 24-hour pharmacokinetic parameters, 24-hour heart rate, 24-hour blood pressure, 24-hour holter monitor, exercise treadmill to induced heart rate, and a 24-hour gastric pH through SmartPill Capsule.

Minimum age: 18 Years. Maximum age: 70 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- 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 UF Health Family Medicine clinic Exclusion Criteria:

- Documented secondary forms of HTN

- 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

- Fistulas

- GI obstruction

- Severe dysphagia

- Crohn's disease

- Diverticulitis

- Any implantable electromedical device

- Use of non-dihydropyridine calcium channel blockers (diltiazem or verapamil)

- Use of digoxin to avoid additive effects on heart rate

Larisa Cavallari, PharmD, Phone: (352) 273-8245, Email: lcavallari@cop.ufl.edu

Family Medicine at Hampton Oaks Medical Plaza, Gainesville, Florida 32607, United States; Not yet recruiting
Sigfried Schmidt, MD, Phone: 352-265-9475, Email: siggy@shands.ufl.edu

Starting date: August 2015
Last updated: April 10, 2015