Impact of Bariatric Surgery on Pharmacokinetic Study of Simvastatin and Carvedilol

February 3, 2022 updated by: Natalia Valadares de Moraes

Impact of Roux-en-Y Gastric Bypass (RYGB) Bariatric Surgery on System Pharmacology: Single-dose Cross-over Pharmacokinetic Study of Simvastatin and Carvedilol.

Obesity affects more than 1 in 3 adults in the U.S. It is commonly associated with reduced quality of life and complications such as metabolic syndrome, heart disease, high blood pressure and sleep disorders. The gastric bypass, also known as Roux-en-Y gastric bypass (RYGB), is one of the most common weight-loss surgeries due to the reliable and long-lasting weight loss and the effective remission of obesity-associated conditions. Although the impact of obesity on absorption, distribution, metabolism and excretion has been documented for several drugs, label recommendations might not account for specific population subgroups, specially morbidly obese patients and obese patients post-bariatric surgery. This study aims to investigate the impact of obesity and RYGB surgery on the kinetic disposition of simvastatin (Study A) and carvedilol (Study B).

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Enrolling by invitation

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

The study is ongoing and eligible subjects are enrolled after signing a written informed consent. Research participants (n=120, in total) include healthy volunteers [body mass index (BMI) ≤ 25 kg/m2], obese [BMI > 30 kg/m2] and patients that underwent RYGB surgery 6-60 month prior this research protocol. On day 1, participants receive a single oral dose of 40 mg simvastatin (Study A) or 25 mg racemic carvedilol (Study B). Serial blood samples are collected up to 24 h for the pharmacokinetic analysis. Blood tests (blood count, fasting blood glucose, lipid profile, serum creatinine, urea, gamma-glutamyl transferase, aspartate aminotransferase and alanine amino transferase) are being monitored for all enrolled participants. Blood samples are also collected for genotyping the main genetic polymorphisms associated with carvedilol or simvastatin pharmacokinetics. Metoprolol is being used as a probe drug for CYP2D6 in vivo phenotyping only for research participants enrolled in Study B. After oral administration of metoprolol (on day 2), urine samples are being collected up to 8h after drug administration to determine the urinary metabolic ratio α-hydroxy metoprolol/metoprolol. As part of the pre-surgery evaluation (obese group) or post-surgery follow-up (RYGB group), obese patients and patients post-RYGB are submitted to digestive endoscopies. Healthy participants will not undergo endoscopic examination. The preparation protocol for digestive endoscopy includes: a) 8-hour fasting; b) 10% spray lidocaine (topical); c) oral simethicone (75 mg/ml, 80 drops); d) oxygen therapy depending on the patient (nasal catheter with O2 at 3 L/min); e) 0.02 to 0.03 mg/kg intravenous midazolam; f) 50 mg pethidine. A blood sample is collected 4-h after intravenous midazolam for in vivo CYP3A4 phenotyping. During the endoscopies, duodenum and jejunum biopsies are being collected to investigated interindividual variability related to drug oral bioavailability (only obese and post-RYGB research participants). Samples collected from digestive biopsies will be used to develop individual enteroid microfluidic systems. In vivo phenotyping of drug metabolizing enzymes and transporters will also be assessed by transcriptome using blood samples. The generated in vitro and in vivo data will be combined to build up physiologically based pharmacokinetic models for precision dosing in obese and post-RYGB patients.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Anticipated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
120

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Florida
      • Orlando, Florida, United States, 32827
        • University of Florida

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Patients of both gender with 18 to 65 years old.
  • Healthy volunteers group: body mass index lower or equal to 35 kg/mˆ2.
  • Obese group: body mass index higher than 30 kg/mˆ2.
  • Post-RYGB group: patients previously submitted to Roux-en-Y gastric bypass bariatric surgery (6-48 months before the study).

Exclusion Criteria:

  • Pregnant and lactating patients.
  • Patients with serum creatinine higher than 1,5 mg/dL.
  • Patients with previous altered coagulation.
  • Patients with previous cancer history (on the last year).
  • Patients with previous hypersensitivity history to simvastatin or carvedilol.
  • Patients who were in use of any anticoagulant (heparin, low molecular weight heparin, aspirin, nonsteroidal antiinflammatory drugs).
  • Patients who were in use of CYP3A4 or P-glycoprotein inhibitors or inducers.
  • For carvedilol study: patients who were in use of CYP2D6 inhibitors; poor metabolizer phenotype of CYP2D6 and genotyped as CYP2C9*3/*3.
  • Patients who disagree to continue the study.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Active Comparator: Simvastatin - Healthy volunteers
Adult patients (18-65 years old) with body mass index < 25 kg/mˆ2 treated with a single oral dose of 40 mg simvastatin for Pk analysis. Blood samples collected for blood tests, genomics and transcriptomic analysis
Procedure: Serial blood sampling for PK analysis
Serial blood samples are being collected at times 0, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 15, 18 and 24 hours after drug administration for PK evaluation .
Drug: Metoprolol 100 mg for CYP2D6 phenotyping
Metoprolol is being used as probe drug to evaluate CYP2D6 activity. Single-dose of metoprolol 100 mg are being administrated orally.
Drug: Simvastatin 40mg
Single-dose of simvastatin 40 mg are being administrated orally.
Other Names:
  • SVA
Drug: Midazolam 2 mg for CYP3A4 phenotyping
Midazolam is being used as probe drug to evaluate CYP3A4 activity. Single-dose of midazolam 2 mg are being administrated intravenous.
Other Names:
  • MDZ
Other: Genotyping
Patients are being genotyped for the main SNP on CYP2C9, ABCB1, SLCO1B1 and CYP2D6 genes using blood samples
Active Comparator: Carvedilol Study - Healthy volunteers
Adult patients (18-65 years old) with body mass index < 25 kg/mˆ2 treated with a single oral dose of 25 mg carvedilol for Pk analysis. Blood samples collected for blood tests, genomics and transcriptomic analysis
Procedure: Serial blood sampling for PK analysis
Serial blood samples are being collected at times 0, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 15, 18 and 24 hours after drug administration for PK evaluation .
Drug: Metoprolol 100 mg for CYP2D6 phenotyping
Metoprolol is being used as probe drug to evaluate CYP2D6 activity. Single-dose of metoprolol 100 mg are being administrated orally.
Drug: Midazolam 2 mg for CYP3A4 phenotyping
Midazolam is being used as probe drug to evaluate CYP3A4 activity. Single-dose of midazolam 2 mg are being administrated intravenous.
Other Names:
  • MDZ
Other: Genotyping
Patients are being genotyped for the main SNP on CYP2C9, ABCB1, SLCO1B1 and CYP2D6 genes using blood samples
Drug: Carvedilol 25mg
Single-dose of carvedilol 25 mg are being administrated orally.
Active Comparator: Simvastatin - Obese
Adult patients (18-65 years old) with body mass index > 30 kg/mˆ2 treated with a single oral dose of 40 mg simvastatin for Pk analysis. Blood samples collected for blood tests, genomics and transcriptomic analysis.
Procedure: Serial blood sampling for PK analysis
Serial blood samples are being collected at times 0, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 15, 18 and 24 hours after drug administration for PK evaluation .
Drug: Metoprolol 100 mg for CYP2D6 phenotyping
Metoprolol is being used as probe drug to evaluate CYP2D6 activity. Single-dose of metoprolol 100 mg are being administrated orally.
Drug: Simvastatin 40mg
Single-dose of simvastatin 40 mg are being administrated orally.
Other Names:
  • SVA
Drug: Midazolam 2 mg for CYP3A4 phenotyping
Midazolam is being used as probe drug to evaluate CYP3A4 activity. Single-dose of midazolam 2 mg are being administrated intravenous.
Other Names:
  • MDZ
Other: Genotyping
Patients are being genotyped for the main SNP on CYP2C9, ABCB1, SLCO1B1 and CYP2D6 genes using blood samples
Procedure: Digestive biopsy
All patients with indication for RYGB bariatric surgery undergo to endoscopy before and after the surgery as standard protocol. Digestive biopsy are being performed in obese and post-RYGB patients for transcriptomic analysis
Active Comparator: Carvedilol study - Obese
Adult patients (18-65 years old) with body mass index > 30 kg/mˆ2 treated with a single oral dose of 25 mg carvedilol for Pk analysis. Blood samples collected for blood tests, genomics and transcriptomic analysis.
Procedure: Serial blood sampling for PK analysis
Serial blood samples are being collected at times 0, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 15, 18 and 24 hours after drug administration for PK evaluation .
Drug: Metoprolol 100 mg for CYP2D6 phenotyping
Metoprolol is being used as probe drug to evaluate CYP2D6 activity. Single-dose of metoprolol 100 mg are being administrated orally.
Drug: Midazolam 2 mg for CYP3A4 phenotyping
Midazolam is being used as probe drug to evaluate CYP3A4 activity. Single-dose of midazolam 2 mg are being administrated intravenous.
Other Names:
  • MDZ
Other: Genotyping
Patients are being genotyped for the main SNP on CYP2C9, ABCB1, SLCO1B1 and CYP2D6 genes using blood samples
Drug: Carvedilol 25mg
Single-dose of carvedilol 25 mg are being administrated orally.
Procedure: Digestive biopsy
All patients with indication for RYGB bariatric surgery undergo to endoscopy before and after the surgery as standard protocol. Digestive biopsy are being performed in obese and post-RYGB patients for transcriptomic analysis
Active Comparator: Simvastatin - Post-RYGB
Adult patients (18-65 years old) previously submitted to RYGB surgery treated with a single oral dose of 40 mg simvastatin for Pk analysis. Blood samples collected for blood tests, genomics and transcriptomic analysis.
Procedure: Serial blood sampling for PK analysis
Serial blood samples are being collected at times 0, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 15, 18 and 24 hours after drug administration for PK evaluation .
Drug: Metoprolol 100 mg for CYP2D6 phenotyping
Metoprolol is being used as probe drug to evaluate CYP2D6 activity. Single-dose of metoprolol 100 mg are being administrated orally.
Drug: Simvastatin 40mg
Single-dose of simvastatin 40 mg are being administrated orally.
Other Names:
  • SVA
Drug: Midazolam 2 mg for CYP3A4 phenotyping
Midazolam is being used as probe drug to evaluate CYP3A4 activity. Single-dose of midazolam 2 mg are being administrated intravenous.
Other Names:
  • MDZ
Other: Genotyping
Patients are being genotyped for the main SNP on CYP2C9, ABCB1, SLCO1B1 and CYP2D6 genes using blood samples
Procedure: Digestive biopsy
All patients with indication for RYGB bariatric surgery undergo to endoscopy before and after the surgery as standard protocol. Digestive biopsy are being performed in obese and post-RYGB patients for transcriptomic analysis
Active Comparator: Carvedilol - Post-RYGB
Adult patients (18-65 years old) previously submitted to RYGB surgery treated with a single oral dose of 25 mg carvedilol for Pk analysis. Blood samples collected for blood tests, genomics and transcriptomic analysis.
Procedure: Serial blood sampling for PK analysis
Serial blood samples are being collected at times 0, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 15, 18 and 24 hours after drug administration for PK evaluation .
Drug: Metoprolol 100 mg for CYP2D6 phenotyping
Metoprolol is being used as probe drug to evaluate CYP2D6 activity. Single-dose of metoprolol 100 mg are being administrated orally.
Drug: Midazolam 2 mg for CYP3A4 phenotyping
Midazolam is being used as probe drug to evaluate CYP3A4 activity. Single-dose of midazolam 2 mg are being administrated intravenous.
Other Names:
  • MDZ
Other: Genotyping
Patients are being genotyped for the main SNP on CYP2C9, ABCB1, SLCO1B1 and CYP2D6 genes using blood samples
Drug: Carvedilol 25mg
Single-dose of carvedilol 25 mg are being administrated orally.
Procedure: Digestive biopsy
All patients with indication for RYGB bariatric surgery undergo to endoscopy before and after the surgery as standard protocol. Digestive biopsy are being performed in obese and post-RYGB patients for transcriptomic analysis

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Pharmacokinetic analysis of simvastatin
Time Frame: Time 0 up to 24 hours after single dose simvastatin administration.
Population pharmacokinetic modeling and simulation.
Time 0 up to 24 hours after single dose simvastatin administration.
Pharmacokinetic analysis of carvedilol
Time Frame: From time 0 up to 24 hours after single dose carvedilol administration
Population pharmacokinetic modeling and simulation.
From time 0 up to 24 hours after single dose carvedilol administration

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
CYP2D6 phenotyping using metoprolol as a probe drug
Time Frame: Urine sampling collected from time 0 up to 8 hours after metoprolol administration
The CYP2D6 phenotype was determined by urinary concentration ratio metoprolol/alfa-hydroxymetoprolol.
Urine sampling collected from time 0 up to 8 hours after metoprolol administration
CYP3A4 phenotyping using midazolam as a probe drug
Time Frame: Day 2: a blood sample will be collected after midazolam administration
Midazolam plasma concentration will be determined by chromatographic analysis
Day 2: a blood sample will be collected after midazolam administration
Genotyping the main SNPs on CYP2C9, CYP2D6, ABCB1 and SLCO1B1 genes
Time Frame: Day 1: a blood sample will be collected immediately after your check-in in the clinical research unit
The main SNPs on CYP2C9, CYP2D6, ABCB1 and SLCO1B1 genes will be evaluated by RT-PCR
Day 1: a blood sample will be collected immediately after your check-in in the clinical research unit
Transcriptomic analysis of liver extracellular vesicles
Time Frame: Day 1: a blood sample will be collected immediately after your check-in in the clinical research unit
Expression levels of transporters and enzymes will be quantified by real-time quantitative PCR
Day 1: a blood sample will be collected immediately after your check-in in the clinical research unit
Transcriptomic analysis of intestine samples
Time Frame: Digestive biopsy collected in the second day of research protocol
Expression levels of transporters and enzymes will be quantified by real-time quantitative PCR
Digestive biopsy collected in the second day of research protocol

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Natalia Valadares de Moraes

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
University of Sao Paulo
Fundação de Amparo à Pesquisa do Estado de São Paulo

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Wilson Salgado Junior, PhD, University of Sao Paulo
  • Principal Investigator: Jose S dos Santos, PhD, University of Sao Paulo
  • Principal Investigator: Natalia De Moraes, PhD, University of Florida

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
June 1, 2019

Primary Completion (Anticipated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
August 1, 2022

Study Completion (Anticipated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
August 1, 2023

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
June 29, 2019

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 7, 2019

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
August 8, 2019

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
February 8, 2022

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
February 3, 2022

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
February 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • RYGB_pk

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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