Hemodialysis, Pharmacokinetics
Conditions
Brief summary
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.
Interventions
DRUGMetoprolol Succinate
Pharmacokinetics
Sponsors
University of Michigan
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age \> 18 years 2. Indwelling tunneled catheter, AVF, AVG that is currently used for hemodialysis 3. Receiving in-center hemodialysis 3 days a week for 3-4.5 hours each treatment 4. Taking a total daily dose of 25-200 mg metoprolol succinate as prescribed by their physician 5. Hemoglobin ≥ 9.5 g/dL on most recent laboratory assessment prior to study
Exclusion criteria
1. Any condition that would not allow for arm BP to be taken 2. Hemoglobin \< 9.5 g/dL on most recent lab prior to study 3. Patient is on a CYP2D6 inhibitor (most common in HD population amiodarone, bupropion, cinacalcet, diphenhydramine, fluoxetine, paroxetine)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Pharmacokinetics-half-life | Pre-dialysis, during dialysis (30 minutes, 2 hours, end of treatment) and post-dialysis (30 minutes, 2 hours and 4 hours) | Characterize the pharmacokinetics of metoprolol and its metabolite, alpha-hydroxymetoprolol during and after HD |
| Plasma Pharmacokinetics-Volume of Distribution | Pre-dialysis, during dialysis (30 minutes, 2 hours, end of treatment) and post-dialysis (30 minutes, 2 hours and 4 hours) | Characterize the pharmacokinetics of metoprolol and its metabolite, alpha-hydroxymetoprolol during and after HD |
| Plasma Pharmacokinetics-elimination rate constant | Pre-dialysis, during dialysis (30 minutes, 2 hours, end of treatment) and post-dialysis (30 minutes, 2 hours and 4 hours) | Characterize the pharmacokinetics of metoprolol and its metabolite, alpha-hydroxymetoprolol during and after HD |
| Plasma pharmacokinetics-Maximal Plasma Concentration | Pre-dialysis, during dialysis (30 minutes, 2 hours, end of treatment) and post-dialysis (30 minutes, 2 hours and 4 hours) | Characterize the pharmacokinetics of metoprolol and its metabolite, alpha-hydroxymetoprolol during and after HD |
| Plasma pharmacokinetics-Time to Maximal Plasma Concentration | Pre-dialysis, during dialysis (30 minutes, 2 hours, end of treatment) and post-dialysis (30 minutes, 2 hours and 4 hours) | Characterize the pharmacokinetics of metoprolol and its metabolite, alpha-hydroxymetoprolol during and after HD |
| Plasma Pharmacokinetics-Area under the concentration time curve (AUC) | Pre-dialysis, during dialysis (30 minutes, 2 hours, end of treatment) and post-dialysis (30 minutes, 2 hours and 4 hours) | Characterize the pharmacokinetics of metoprolol and its metabolite, alpha-hydroxymetoprolol during and after HD |
| Plasma Pharmacokinetics-Clearance | Pre-dialysis, during dialysis (30 minutes, 2 hours, end of treatment) and post-dialysis (30 minutes, 2 hours and 4 hours) | Characterize the pharmacokinetics of metoprolol and its metabolite, alpha-hydroxymetoprolol during and after HD |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Post-dialysis Rebound | post-dialysis (30 minutes, 2 hours and 4 hours) | Simulate predicted rebound of metoprolol concentrations |
| Non-renal clearance phenotype and genotype | Pre-dialysis, during dialysis (30 minutes, 2 hours, end of treatment) and post-dialysis (30 minutes, 2 hours and 4 hours) | Evaluate the non-renal clearance of metoprolol in patients on HD |
Countries
United States
Outcome results
None listed