Clinical trial NCT02417246: Open-Labeled PK-PD Studies of Metoprolol ER
Official title: Open-Labeled Pharmacokinetic and Pharmacodynamic (PK-PD) Studies of Metoprolol ER
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Blood Pressure
Keywords: pharmacokinetics
pharmacodynamics
pharmacogenetics
Lead sponsor: University of Florida
Sponsor class: OTHER
Collaborators: name: Food and Drug Administration (FDA)
First posted: 2015-04-15
Enrollment: 61
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

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.

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 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.

Eligibility 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 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

Primary outcomes:
measure: Area Under the Plasma Concentration Versus Time Curve (AUC)
timeFrame: 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
measure: Peak Plasma Concentration (Cmax) of Metoprolol Succinate
timeFrame: 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:
measure: The Heart Rate Variability (HRV) Response to Brand Name Metoprolol ER Versus Each Generic Formulation of Metoprolol Succinate.
timeFrame: Heart rate variability (Low-to-High Frequency Ratio) over each quartile of 6 hours in the 24-hr period
measure: Blood Pressure Values (Systolic and Diastolic) Compared Between Brand Name Metoprolol ER and Each Generic Metoprolol Formulation (Generic B, Generic A)
timeFrame: Average value over each quartile of 6 hours in the 24-hr period
measure: Heart Rate (HR) Response Compared Between Brand Name Metoprolol ER and Each Generic (Generic B, Generic A) Formulation of Metoprolol Succinate
timeFrame: Average value over each quartile of 6 hours in the 24-hr period
Other outcomes:
Locations:
city: Gainesville
country: United States
facility: Family Medicine at Hampton Oaks Medical Plaza
state: Florida
city: Gainesville
country: United States
facility: Oak Hammock at the University of Florida
state: Florida
Study officials:
affiliation: University of Florida
name: Larisa Cavallari, PharmD
role: PRINCIPAL_INVESTIGATOR
References: