Impact of Bariatric Surgery on Pharmacokinetic Study of Simvastatin and Carvedilol
- Conditions
- Bariatric SurgeryObesityRoux-en Y Gastric Bypass
- Interventions
- Procedure: Serial blood sampling for PK analysisProcedure: Digestive biopsyOther: Genotyping
- Registration Number
- NCT04049786
- Lead Sponsor
- Natalia Valadares de Moraes
- 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.
Recruitment & Eligibility
- Status
- UNKNOWN
- Sex
- All
- Target Recruitment
- 120
- 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).
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Simvastatin - Healthy volunteers Simvastatin 40mg 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 Simvastatin - Healthy volunteers Midazolam 2 mg for CYP3A4 phenotyping 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 Carvedilol Study - Healthy volunteers Midazolam 2 mg for CYP3A4 phenotyping 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 Carvedilol study - Obese Midazolam 2 mg for CYP3A4 phenotyping 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. Simvastatin - Post-RYGB Simvastatin 40mg 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. Simvastatin - Obese Simvastatin 40mg 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. Simvastatin - Obese Midazolam 2 mg for CYP3A4 phenotyping 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. Carvedilol - Post-RYGB Midazolam 2 mg for CYP3A4 phenotyping 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. Simvastatin - Post-RYGB Midazolam 2 mg for CYP3A4 phenotyping 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. Carvedilol - Post-RYGB Carvedilol 25mg 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. Carvedilol Study - Healthy volunteers Metoprolol 100 mg for CYP2D6 phenotyping 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 Carvedilol - Post-RYGB Metoprolol 100 mg for CYP2D6 phenotyping 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. Simvastatin - Healthy volunteers Serial blood sampling for PK analysis 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 Simvastatin - Healthy volunteers Metoprolol 100 mg for CYP2D6 phenotyping 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 Simvastatin - Obese Metoprolol 100 mg for CYP2D6 phenotyping 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. Carvedilol Study - Healthy volunteers Carvedilol 25mg 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 Simvastatin - Obese Genotyping 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. Carvedilol study - Obese Carvedilol 25mg 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. Carvedilol study - Obese Serial blood sampling for PK analysis 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. Simvastatin - Post-RYGB Digestive biopsy 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. Carvedilol - Post-RYGB Genotyping 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. Simvastatin - Obese Digestive biopsy 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. Simvastatin - Healthy volunteers Genotyping 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 Carvedilol Study - Healthy volunteers Serial blood sampling for PK analysis 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 Carvedilol study - Obese Digestive biopsy 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. Simvastatin - Post-RYGB Metoprolol 100 mg for CYP2D6 phenotyping 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. Carvedilol Study - Healthy volunteers Genotyping 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 Carvedilol study - Obese Metoprolol 100 mg for CYP2D6 phenotyping 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. Simvastatin - Post-RYGB Serial blood sampling for PK analysis 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. Simvastatin - Obese Serial blood sampling for PK analysis 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. Simvastatin - Post-RYGB Genotyping 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. Carvedilol study - Obese Genotyping 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. Carvedilol - Post-RYGB Digestive biopsy 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. Carvedilol - Post-RYGB Serial blood sampling for PK analysis 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.
- Primary Outcome Measures
Name Time Method Pharmacokinetic analysis of simvastatin Time 0 up to 24 hours after single dose simvastatin administration. Population pharmacokinetic modeling and simulation.
Pharmacokinetic analysis of carvedilol From time 0 up to 24 hours after single dose carvedilol administration Population pharmacokinetic modeling and simulation.
- Secondary Outcome Measures
Name Time Method CYP3A4 phenotyping using midazolam as a probe drug Day 2: a blood sample will be collected after midazolam administration Midazolam plasma concentration will be determined by chromatographic analysis
Transcriptomic analysis of liver extracellular vesicles 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
CYP2D6 phenotyping using metoprolol as a probe drug 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.
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 The main SNPs on CYP2C9, CYP2D6, ABCB1 and SLCO1B1 genes will be evaluated by RT-PCR
Transcriptomic analysis of intestine samples Digestive biopsy collected in the second day of research protocol Expression levels of transporters and enzymes will be quantified by real-time quantitative PCR
Trial Locations
- Locations (1)
University of Florida
🇺🇸Orlando, Florida, United States