Impact of Bariatric Surgery on Pharmacokinetic Study of Simvastatin and Carvedilol

NCT04049786 | Unknown Phase 4 FDA Drug

• 1 other identifier: RYGB_pk
• Study Type: interventional
• Target: 120
• Locations: 1 country
• Sites: 1

Brief Summary

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).

Conditions

Obesity; Bariatric Surgery; Roux-en Y Gastric Bypass

Keywords

Bariatric surgery; Pharmacokinetics; RYGB; CYP2D6; CYP3A4

Outcome Measures

Primary Outcomes (2)

• Pharmacokinetic analysis of simvastatin

  Population pharmacokinetic modeling and simulation.

  Time 0 up to 24 hours after single dose simvastatin administration.

• Pharmacokinetic analysis of carvedilol

  Population pharmacokinetic modeling and simulation.

  From time 0 up to 24 hours after single dose carvedilol administration

Secondary Outcomes (5)

• CYP2D6 phenotyping using metoprolol as a probe drug

  Urine sampling collected from time 0 up to 8 hours after metoprolol administration

• CYP3A4 phenotyping using midazolam as a probe drug

  Day 2: a blood sample will be collected after midazolam administration

• Genotyping the main SNPs on CYP2C9, CYP2D6, ABCB1 and SLCO1B1 genes

  Day 1: a blood sample will be collected immediately after your check-in in the clinical research unit

• Transcriptomic analysis of liver extracellular vesicles

  Day 1: a blood sample will be collected immediately after your check-in in the clinical research unit

• Transcriptomic analysis of intestine samples

  Digestive biopsy collected in the second day of research protocol

Study Arms (6)

Simvastatin - Healthy volunteers

ACTIVE COMPARATOR

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; Drug: Metoprolol 100 mg for CYP2D6 phenotyping; Drug: Simvastatin 40mg; Drug: Midazolam 2 mg for CYP3A4 phenotyping; Other: Genotyping

Carvedilol Study - Healthy volunteers

ACTIVE COMPARATOR

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

Drug: Carvedilol 25mg; Procedure: Serial blood sampling for PK analysis; Drug: Metoprolol 100 mg for CYP2D6 phenotyping; Drug: Midazolam 2 mg for CYP3A4 phenotyping; Other: Genotyping

Simvastatin - Obese

ACTIVE COMPARATOR

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: Digestive biopsy; Procedure: Serial blood sampling for PK analysis; Drug: Metoprolol 100 mg for CYP2D6 phenotyping; Drug: Simvastatin 40mg; Drug: Midazolam 2 mg for CYP3A4 phenotyping; Other: Genotyping

Carvedilol study - Obese

ACTIVE COMPARATOR

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: Digestive biopsy; Drug: Carvedilol 25mg; Procedure: Serial blood sampling for PK analysis; Drug: Metoprolol 100 mg for CYP2D6 phenotyping; Drug: Midazolam 2 mg for CYP3A4 phenotyping; Other: Genotyping

Simvastatin - Post-RYGB

ACTIVE COMPARATOR

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: Digestive biopsy; Procedure: Serial blood sampling for PK analysis; Drug: Metoprolol 100 mg for CYP2D6 phenotyping; Drug: Simvastatin 40mg; Drug: Midazolam 2 mg for CYP3A4 phenotyping; Other: Genotyping

Carvedilol - Post-RYGB

ACTIVE COMPARATOR

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: Digestive biopsy; Drug: Carvedilol 25mg; Procedure: Serial blood sampling for PK analysis; Drug: Metoprolol 100 mg for CYP2D6 phenotyping; Drug: Midazolam 2 mg for CYP3A4 phenotyping; Other: Genotyping

Interventions

Digestive biopsy PROCEDURE

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

Carvedilol - Post-RYGB; Carvedilol study - Obese; Simvastatin - Obese; Simvastatin - Post-RYGB

Carvedilol 25mg DRUG

Single-dose of carvedilol 25 mg are being administrated orally.

Carvedilol - Post-RYGB; Carvedilol Study - Healthy volunteers; Carvedilol study - Obese

Serial blood sampling for PK analysis PROCEDURE

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 .

Carvedilol - Post-RYGB; Carvedilol Study - Healthy volunteers; Carvedilol study - Obese; Simvastatin - Healthy volunteers; Simvastatin - Obese; Simvastatin - Post-RYGB

Metoprolol 100 mg for CYP2D6 phenotyping DRUG

Metoprolol is being used as probe drug to evaluate CYP2D6 activity. Single-dose of metoprolol 100 mg are being administrated orally.

Carvedilol - Post-RYGB; Carvedilol Study - Healthy volunteers; Carvedilol study - Obese; Simvastatin - Healthy volunteers; Simvastatin - Obese; Simvastatin - Post-RYGB

Simvastatin 40mg DRUG

Single-dose of simvastatin 40 mg are being administrated orally.

Also known as: SVA

Simvastatin - Healthy volunteers; Simvastatin - Obese; Simvastatin - Post-RYGB

Midazolam 2 mg for CYP3A4 phenotyping DRUG

Midazolam is being used as probe drug to evaluate CYP3A4 activity. Single-dose of midazolam 2 mg are being administrated intravenous.

Also known as: MDZ

Carvedilol - Post-RYGB; Carvedilol Study - Healthy volunteers; Carvedilol study - Obese; Simvastatin - Healthy volunteers; Simvastatin - Obese; Simvastatin - Post-RYGB

Genotyping OTHER

Patients are being genotyped for the main SNP on CYP2C9, ABCB1, SLCO1B1 and CYP2D6 genes using blood samples

Carvedilol - Post-RYGB; Carvedilol Study - Healthy volunteers; Carvedilol study - Obese; Simvastatin - Healthy volunteers; Simvastatin - Obese; Simvastatin - Post-RYGB

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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.

Sponsors & Collaborators

• Natalia Valadares de Moraes: lead
• Fundação de Amparo à Pesquisa do Estado de São Paulo: collaborator
• University of Sao Paulo: collaborator

Study Sites (1)

University of Florida

Orlando, Florida, 32827, United States

Location

MeSH Terms

Conditions

Obesity

Interventions

Carvedilol; Metoprolol; Simvastatin; Midazolam; Genotype

Condition Hierarchy (Ancestors)

Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines; Carbazoles; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 3-Ring; Phenoxypropanolamines; Lovastatin; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds; Benzodiazepines; Benzazepines; Genetic Phenomena

Study Officials

• 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

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: June 29, 2019
• First Posted: August 8, 2019
• Study Start: June 1, 2019
• Primary Completion: August 1, 2022
• Study Completion: August 1, 2023
• Last Updated: February 8, 2022

Record last verified: 2022-02

Locations

US (1)