Pharmacogenetic Prediction of Metoprolol Effectiveness

Study Overview
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Brief Summary
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The investigators will prospectively follow a population of patients with uncontrolled high blood pressure beginning metoprolol succinate therapy to determine the drug effect in an observational clinical trial. The investigators will determine each individual's genotype for both CYP2D6 and Adrenoceptor Beta 1 (ADRB1). Metabolomic markers will be identified to determine if specific metabolites are associated with drug response. The investigators' overall objective is to determine if genetics predicts metoprolol succinate response better than clinical factors such as age, race, body mass index, dose, and medication co-ingestion.

Official Title
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Pharmacogenetic Prediction of Metoprolol Effectiveness

Conditions
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Hypertension

Intervention / Treatment
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* Drug: metoprolol succinate
* Genetic: Genotyping
* Procedure: CYP2D6 Phenotyping


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects between age >30 years and < 80 years Subjects have diagnosis of uncontrolled essential hypertension. Exclusion Criteria: end stage liver disease, end stage renal disease, pregnant females, American Society of Anesthesiologists (ASA) classification of >3, wards of the state, prisoners, decisionally challenged, HR<60 bpm, AV block>240 msec, active reactive airway disease, illicit drug abuse in the preceding 30 days, hypersensitivity to metoprolol or its derivatives severe peripheral arterial circulatory disorders. Subjects will have a screening physical exam performed by Dr. Monte prior to enrollment in the study.

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 80 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: Treatment
Intervention Model: Single Group Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metoprolol succinate, CYP2D6 Genotyping, CYP2D6 Phenotyping<br>The parent study will integrate covariates to predict metoprolol effectiveness for SBP decline of 10%. All patients will receive metoprolol. The following covariates will be used to predict metoprolol effectiveness: clinical variables (Age, sex, race/ethnicity, co-medications, and BMI) CYP2D6 genotype, CYP2D6 phenotype, and metabolomic factors. metoprolol succinate Genotyping: CYP2D6 only clinically pertinent pathway of metoprolol metabolism and polymorphisms have been associated with altered levels of metoprolol. ADRB1 is the drug target and polymorphism in this receptor has been associated with variable drug response. Genotyping will occur after the treatment phase is complete. CYP2D6 Phenotyping: Phenotype can be discordant from what is predicted by genotype. CYP2D6 henotyping using dextromethorphan will be used. Investigators will be blind to the patient blood pressure outcome for this intervention. | Drug: metoprolol succinate<br> <br> * Other names: Lopressor;Genetic: Genotyping<br>* CYP2D6 only clinically pertinent pathway of metoprolol metabolism and polymorphisms have been associated with altered levels of metoprolol. ADRB1 is the drug target and polymorphism in this receptor has been associated with variable drug response. Genotyping will occur after the treatment phase is complete. Thus the investigator, the subject, and the outcomes investigator will be blind to the intervention.<br>* Other names: CYP2D6 genotyping and ADRB1 genotyping;Procedure: CYP2D6 Phenotyping<br>* Phenotype can be discordant from what is predicted by genotype due to variability in absorption, hepatic blood flow, drug interaction and drug elimination. These factors can be accounted for by utilizing a phenotyping assay that determines area under the curve of the probe since the probe is affected by the same variables dictating metabolism phenotype of the therapeutic drug. Investigators will be blind to the patient blood pressure outcome for this intervention.<br>* Other names: Dextromethorphan probe of CYP2D6;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood Pressure Decline | Participants with at least a 10% decrease in SBP | 4-6 weeks status post initiation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Heart Rate Decline | 10 % decline from pre-initiation heart rate will considered a HR decline success. Number of of participants with at least 10% decline is reported. | 4-6 weeks | 
| Adverse Drug Events: CYP2D6 Metabolizer Status | Occurrence of adverse drug events will be captured and stratified by CYP2D6 metabolizer status (Poor Metabolizer (PM), Extensive Metabolizer (EM), Intermediate Metabolizer (IM), and Ultra rapid Metabolizer). | 6 weeks | 
| Adverse Drug Events: ADRB1 Genotype | Occurrence of adverse drug events will be captured and stratified by ADRB1 genotype (strong responder, good responder, non-responder). | 6 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Genotype, CYP2D6, ADRB1