Evaluation of Metoprolol Pharmacokinetics in Patients Receiving Hi Flux Hemodialysis

Study Overview
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Brief Summary
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The current study will evaluate the plasma pharmacokinetics of metoprolol in a cohort of 8 adult volunteers who are receiving regular hemodialysis treatment (HD) 3 days a week for 4 hours each day and have been taking a total daily dose of 25-200 mg of metoprolol succinate for >30 days as part of their usual care. Blood sampling will occur over 10 hours, with frequent sampling during HD and in the 4 hours after termination of HD treatment. The 8 subjects will all receive their prescribed dose (25-200 mg total daily dose) 2 hours prior to HD treatment. The pre-HD sample will also be sent for pharmacogenomics genotyping. Safety and pharmacodynamic assessments (blood pressure (BP) and heart rate (HR) assessments) will be performed throughout the study. Axiom Precision Medicine Research Array (Affymetrix, Santa Clara, CA) will be used to evaluate genotype of CYP2D6. CYP2D6 phenotype will be evaluated using the ratio of parent drug to metabolite. Non-compartmental analyses will be performed to compare maximum concentrations (Cmax), time to maximum concentration and area under the curve from time 0 to the last measurable sample (AUClast) between the two phases. Compartmental analyses will be performed to construct a model to explain time-dependent changes in metoprolol clearance. Monte Carlo simulations will be performed to compare metoprolol pharmacokinetic profiles on and off HD.

Official Title
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Evaluation of Metoprolol Pharmacokinetics in Patients Receiving Hi Flux Hemodialysis

Conditions
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Hemodialysis, Pharmacokinetics

Intervention / Treatment
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* Drug: Metoprolol Succinate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age > 18 years Indwelling tunneled catheter, AVF, AVG that is currently used for hemodialysis Receiving in-center hemodialysis 3 days a week for 3-4.5 hours each treatment Taking a total daily dose of 25-200 mg metoprolol succinate as prescribed by their physician Hemoglobin ≥ 9.5 g/dL on most recent laboratory assessment prior to study Exclusion Criteria: Any condition that would not allow for arm BP to be taken Hemoglobin < 9.5 g/dL on most recent lab prior to study Patient is on a CYP2D6 inhibitor (most common in HD population amiodarone, bupropion, cinacalcet, diphenhydramine, fluoxetine, paroxetine)

Ages Eligible for Study
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Minimum Age: 18 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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Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: Metoprolol Succinate|Pharmacokinetics|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma pharmacokinetics-Maximal Plasma Concentration | Characterize the pharmacokinetics of metoprolol and its metabolite, alpha-hydroxymetoprolol during and after HD | Pre-dialysis, during dialysis (30 minutes, 2 hours, end of treatment) and post-dialysis (30 minutes, 2 hours and 4 hours) | 
| Plasma pharmacokinetics-Time to Maximal Plasma Concentration | Characterize the pharmacokinetics of metoprolol and its metabolite, alpha-hydroxymetoprolol during and after HD | Pre-dialysis, during dialysis (30 minutes, 2 hours, end of treatment) and post-dialysis (30 minutes, 2 hours and 4 hours) | 
| Plasma Pharmacokinetics-Area under the concentration time curve (AUC) | Characterize the pharmacokinetics of metoprolol and its metabolite, alpha-hydroxymetoprolol during and after HD | Pre-dialysis, during dialysis (30 minutes, 2 hours, end of treatment) and post-dialysis (30 minutes, 2 hours and 4 hours) | 
| Plasma Pharmacokinetics-Clearance | Characterize the pharmacokinetics of metoprolol and its metabolite, alpha-hydroxymetoprolol during and after HD | Pre-dialysis, during dialysis (30 minutes, 2 hours, end of treatment) and post-dialysis (30 minutes, 2 hours and 4 hours) | 
| Plasma Pharmacokinetics-Volume of Distribution | Characterize the pharmacokinetics of metoprolol and its metabolite, alpha-hydroxymetoprolol during and after HD | Pre-dialysis, during dialysis (30 minutes, 2 hours, end of treatment) and post-dialysis (30 minutes, 2 hours and 4 hours) | 
| Plasma Pharmacokinetics-elimination rate constant | Characterize the pharmacokinetics of metoprolol and its metabolite, alpha-hydroxymetoprolol during and after HD | Pre-dialysis, during dialysis (30 minutes, 2 hours, end of treatment) and post-dialysis (30 minutes, 2 hours and 4 hours) | 
| Plasma Pharmacokinetics-half-life | Characterize the pharmacokinetics of metoprolol and its metabolite, alpha-hydroxymetoprolol during and after HD | Pre-dialysis, during dialysis (30 minutes, 2 hours, end of treatment) and post-dialysis (30 minutes, 2 hours and 4 hours) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Non-renal clearance phenotype and genotype | Evaluate the non-renal clearance of metoprolol in patients on HD | Pre-dialysis, during dialysis (30 minutes, 2 hours, end of treatment) and post-dialysis (30 minutes, 2 hours and 4 hours) | 
| Post-dialysis Rebound | Simulate predicted rebound of metoprolol concentrations | post-dialysis (30 minutes, 2 hours and 4 hours) |