Impact of Bariatric Surgery on Pharmacokinetic Study of Simvastatin and Carvedilol

NCT ID: NCT04049786

Last Updated: 2022-02-08

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE4
• Total Enrollment: 120 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-06-01
• Study Completion Date: 2023-08-31

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).

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.

Conditions

Obesity; Bariatric Surgery; Roux-en Y Gastric Bypass

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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

Group Type: ACTIVE_COMPARATOR

Serial blood sampling for PK analysis

Intervention Type: 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 .

Metoprolol 100 mg for CYP2D6 phenotyping

Intervention Type: DRUG

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

Simvastatin 40mg

Intervention Type: DRUG

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

Midazolam 2 mg for CYP3A4 phenotyping

Intervention Type: DRUG

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

Genotyping

Intervention Type: OTHER

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

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

Group Type: ACTIVE_COMPARATOR

Carvedilol 25mg

Intervention Type: DRUG

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

Serial blood sampling for PK analysis

Intervention Type: 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 .

Metoprolol 100 mg for CYP2D6 phenotyping

Intervention Type: DRUG

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

Midazolam 2 mg for CYP3A4 phenotyping

Intervention Type: DRUG

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

Genotyping

Intervention Type: OTHER

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

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.

Group Type: ACTIVE_COMPARATOR

Digestive biopsy

Intervention Type: 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

Serial blood sampling for PK analysis

Intervention Type: 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 .

Metoprolol 100 mg for CYP2D6 phenotyping

Intervention Type: DRUG

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

Simvastatin 40mg

Intervention Type: DRUG

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

Midazolam 2 mg for CYP3A4 phenotyping

Intervention Type: DRUG

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

Genotyping

Intervention Type: OTHER

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

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.

Group Type: ACTIVE_COMPARATOR

Digestive biopsy

Intervention Type: 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 25mg

Intervention Type: DRUG

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

Serial blood sampling for PK analysis

Intervention Type: 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 .

Metoprolol 100 mg for CYP2D6 phenotyping

Intervention Type: DRUG

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

Midazolam 2 mg for CYP3A4 phenotyping

Intervention Type: DRUG

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

Genotyping

Intervention Type: OTHER

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

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.

Group Type: ACTIVE_COMPARATOR

Digestive biopsy

Intervention Type: 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

Serial blood sampling for PK analysis

Intervention Type: 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 .

Metoprolol 100 mg for CYP2D6 phenotyping

Intervention Type: DRUG

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

Simvastatin 40mg

Intervention Type: DRUG

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

Midazolam 2 mg for CYP3A4 phenotyping

Intervention Type: DRUG

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

Genotyping

Intervention Type: OTHER

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

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.

Group Type: ACTIVE_COMPARATOR

Digestive biopsy

Intervention Type: 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 25mg

Intervention Type: DRUG

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

Serial blood sampling for PK analysis

Intervention Type: 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 .

Metoprolol 100 mg for CYP2D6 phenotyping

Intervention Type: DRUG

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

Midazolam 2 mg for CYP3A4 phenotyping

Intervention Type: DRUG

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

Genotyping

Intervention Type: OTHER

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

Interventions

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

Intervention Type: PROCEDURE

Carvedilol 25mg

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

Intervention Type: DRUG

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 .

Intervention Type: PROCEDURE

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.

Intervention Type: DRUG

Simvastatin 40mg

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

Intervention Type: 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.

Intervention Type: DRUG

Genotyping

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

Intervention Type: OTHER

Other Intervention Names

SVA; MDZ

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Fundação de Amparo à Pesquisa do Estado de São Paulo

OTHER_GOV

Sponsor Role: collaborator

University of Sao Paulo

OTHER

Sponsor Role: collaborator

Natalia Valadares de Moraes

OTHER

Sponsor Role: lead

Responsible Party

Natalia Valadares de Moraes

Assistant Professor

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Wilson Salgado Junior, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Sao Paulo

Jose S dos Santos, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Sao Paulo

Natalia De Moraes, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Florida

Locations

University of Florida

Orlando, Florida, United States

Countries

United States

Other Identifiers

RYGB_pk

Identifier Type: -

Identifier Source: org_study_id