Impact of Roux-en-Y Gastric Bypass (RYGB) Bariatric Surgery on System Pharmacology: Single-dose Cross-over Pharmacokinetic Study of Simvastatin and Carvedilol.
试验速览
- 阶段
- 4 期
- 发起方
- 入组人数
- 120
- 试验地点
- 1
- 主要终点
- Pharmacokinetic analysis of simvastatin
研究概览
简要总结
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).
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients of both gender with 18 to 65 years old.
- •Healthy volunteers group: body mass index lower or equal to 35 kg/mˆ
- •Obese group: body mass index higher than 30 kg/mˆ
- •Post-RYGB group: patients previously submitted to Roux-en-Y gastric bypass bariatric surgery (6-48 months before the study).
排除标准
- •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/*
- •Patients who disagree to continue the study.
研究组 & 干预措施
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
干预措施: Genotyping (Other)
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
干预措施: Serial blood sampling for PK analysis (Procedure)
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
干预措施: Metoprolol 100 mg for CYP2D6 phenotyping (Drug)
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
干预措施: Simvastatin 40mg (Drug)
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
干预措施: Midazolam 2 mg for CYP3A4 phenotyping (Drug)
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
干预措施: Carvedilol 25mg (Drug)
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
干预措施: Serial blood sampling for PK analysis (Procedure)
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
干预措施: Metoprolol 100 mg for CYP2D6 phenotyping (Drug)
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
干预措施: Midazolam 2 mg for CYP3A4 phenotyping (Drug)
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
干预措施: Genotyping (Other)
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.
干预措施: Digestive biopsy (Procedure)
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.
干预措施: Serial blood sampling for PK analysis (Procedure)
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.
干预措施: Metoprolol 100 mg for CYP2D6 phenotyping (Drug)
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.
干预措施: Simvastatin 40mg (Drug)
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.
干预措施: Midazolam 2 mg for CYP3A4 phenotyping (Drug)
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.
干预措施: Genotyping (Other)
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.
干预措施: Digestive biopsy (Procedure)
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.
干预措施: Carvedilol 25mg (Drug)
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.
干预措施: Serial blood sampling for PK analysis (Procedure)
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.
干预措施: Metoprolol 100 mg for CYP2D6 phenotyping (Drug)
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.
干预措施: Midazolam 2 mg for CYP3A4 phenotyping (Drug)
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.
干预措施: Genotyping (Other)
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.
干预措施: Digestive biopsy (Procedure)
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.
干预措施: Serial blood sampling for PK analysis (Procedure)
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.
干预措施: Metoprolol 100 mg for CYP2D6 phenotyping (Drug)
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.
干预措施: Simvastatin 40mg (Drug)
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.
干预措施: Midazolam 2 mg for CYP3A4 phenotyping (Drug)
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.
干预措施: Genotyping (Other)
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.
干预措施: Digestive biopsy (Procedure)
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.
干预措施: Carvedilol 25mg (Drug)
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.
干预措施: Serial blood sampling for PK analysis (Procedure)
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.
干预措施: Metoprolol 100 mg for CYP2D6 phenotyping (Drug)
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.
干预措施: Midazolam 2 mg for CYP3A4 phenotyping (Drug)
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.
干预措施: Genotyping (Other)
结局指标
主要结局
Pharmacokinetic analysis of simvastatin
时间窗: Time 0 up to 24 hours after single dose simvastatin administration.
Population pharmacokinetic modeling and simulation.
Pharmacokinetic analysis of carvedilol
时间窗: From time 0 up to 24 hours after single dose carvedilol administration
Population pharmacokinetic modeling and simulation.
次要结局
- CYP3A4 phenotyping using midazolam as a probe drug(Day 2: a blood sample will be collected after midazolam administration)
- Transcriptomic analysis of liver extracellular vesicles(Day 1: a blood sample will be collected immediately after your check-in in the clinical research unit)
- CYP2D6 phenotyping using metoprolol as a probe drug(Urine sampling collected from time 0 up to 8 hours after metoprolol 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 intestine samples(Digestive biopsy collected in the second day of research protocol)
研究者
Natalia Valadares de Moraes
Assistant Professor
Universidade Estadual Paulista Júlio de Mesquita Filho