Open-Labeled PK-PD Studies of Metoprolol ER

Study Overview
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Brief Summary
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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.

Detailed Description
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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 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 Sequence A- start with brand name metoprolol ER, switch to Generic B metoprolol, switch back to brand name metoprolol ER, then switch to Generic A metoprolol Study Sequence B- start with brand name metoprolol ER, switch to Generic A metoprolol, switch back to brand name metoprolol ER, then switch to Generic B metoprolol. Each study sequence will consist of treatment with brand name metoprolol ER for 2 periods, treatment with Generic A metoprolol ER for one period, and treatment with Generic B metoprolol ER 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 parameter assessment, 24-hour heart rate monitoring, 24-hour blood pressure monitoring, 24-hour holter monitoring, exercise treadmill to induce heart rate, and a 24-hour gastric potential hydrogen (pH) monitoring via a wireless capsule.

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

Conditions
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Blood Pressure

Intervention / Treatment
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* Drug: brand name metoprolol ER
* Drug: Generic A
* Drug: Generic B


Participation Criteria
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Eligibility Criteria
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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 University of Florida Health Family Medicine clinic or through other means. Exclusion Criteria: 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 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Study Sequence A<br>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<br>* This medication will be taken for 7 to 28 days<br>* Other names: Metoprolol extended-release (ER);Drug: Generic A<br>* This medication will be taken for 7 days<br>* Other names: Metoprolol extended-release (ER);Drug: Generic B<br>* This medication will be taken for 7 days<br>* Other names: Metoprolol extended-release (ER);|
| Active Comparator: Study Sequence B<br>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<br>* This medication will be taken for 7 to 28 days<br>* Other names: Metoprolol extended-release (ER);Drug: Generic A<br>* This medication will be taken for 7 days<br>* Other names: Metoprolol extended-release (ER);Drug: Generic B<br>* This medication will be taken for 7 days<br>* Other names: Metoprolol extended-release (ER);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Heart Rate Variability (HRV) Response to Brand Name Metoprolol ER Versus Each Generic Formulation of Metoprolol Succinate. | 24-h digital heart rate monitor analyses were obtained after Phase 1 (brand name metoprolol ER ), Phase 2 (Generic B or Generic A), and Phase 4 (Generic A or Generic B). Data were analyzed by quartiles. One 5-minute epoch from each hour of each quartile was selected based on absence of a significant number of ectopic beats and artifact from which spectral measures were calculated: high-frequency variability (measure of parasympathetic activity), low-frequency variability (measure of sympathetic activity). The ratio of low-to-high frequency variability was calculated for each quartile. The averages of values obtained for each hour of each quartile constituted the final quartile measures that were used for analysis. The low to high frequency ratio obtained for each quartile represents the balance between sympathetic and parasympathetic nervous system activity and was the primary variable for heart rate variability analysis. | 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) | 24-hr ambulatory blood pressure (BP) recordings taken 4 times per hour (every 15 minutes) between 6AM and 11PM and 2 times per hour (every 30 minutes) 11PM and 6AM were obtained after Phase 1 (Brand name metoprolol ER), Phase 2 (Generic B or Generic A), and Phase 4 (Generic A or Generic B). | 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 | 24-h ambulatory heart rate recordings taken 4 times per hour (every 15 minutes) between 6AM and 11PM and 2 times per hour (every 30 minutes) 11PM and 6AM were obtained after Phase 1 (brand name metoprolol ER), Phase 2 (Generic B or Generic A), and Phase 4 (Generic A or Generic B) | Average value over each quartile of 6 hours in the 24-hr period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pharmacokinetics, pharmacodynamics, pharmacogenetics