Pharmacogenetic Prediction of Metoprolol Effectiveness

University of Colorado Denver (CU Denver)

Status: Terminated

Conditions: Hypertension

Treatments: Procedure: CYP2D6 Phenotyping; Drug: metoprolol succinate; Genetic: Genotyping

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT02293096

1K23GM110516-01 (U.S. NIH Grant/Contract)

13-3174

Details and patient eligibility

About

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.

Enrollment: 462 patients

Sex: All

Ages: 30 to 80 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. Subjects between age >30 years and < 80 years
2. Subjects have diagnosis of uncontrolled essential hypertension.

Exclusion criteria

1. end stage liver disease,
2. end stage renal disease,
3. pregnant females,
4. American Society of Anesthesiologists (ASA) classification of >3,
5. wards of the state, prisoners,
6. decisionally challenged,
7. HR<60 bpm,
8. AV block>240 msec,
9. active reactive airway disease,
10. illicit drug abuse in the preceding 30 days,
11. hypersensitivity to metoprolol or its derivatives
12. severe peripheral arterial circulatory disorders.

Subjects will have a screening physical exam performed by Dr. Monte prior to enrollment in the study.

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: Quadruple Blind

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462 participants in 1 patient group

Metoprolol succinate, CYP2D6 Genotyping, CYP2D6 Phenotyping

Experimental group

Description:

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.

Treatment:

Genetic: Genotyping

Drug: metoprolol succinate

Procedure: CYP2D6 Phenotyping