Clinical trial NCT04049786: Impact of Bariatric Surgery on Pharmacokinetic Study of Simvastatin and Carvedilol
Official title: Impact of Roux-en-Y Gastric Bypass (RYGB) Bariatric Surgery on System Pharmacology: Single-dose Cross-over Pharmacokinetic Study of Simvastatin and Carvedilol.
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Obesity
Bariatric Surgery
Roux-en Y Gastric Bypass
Keywords: Bariatric surgery
Pharmacokinetics
RYGB
CYP2D6
CYP3A4
Lead sponsor: Universidade Estadual Paulista Júlio de Mesquita Filho
Sponsor class: OTHER
Collaborators: name: Fundação de Amparo à Pesquisa do Estado de São Paulo
name: University of Sao Paulo
First posted: 2019-08-08
Enrollment: 120
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Pharmacokinetic analysis of simvastatin
timeFrame: Time 0 up to 24 hours after single dose simvastatin administration.
measure: Pharmacokinetic analysis of carvedilol
timeFrame: From time 0 up to 24 hours after single dose carvedilol administration
Secondary outcomes:
measure: CYP2D6 phenotyping using metoprolol as a probe drug
timeFrame: Urine sampling collected from time 0 up to 8 hours after metoprolol administration
measure: CYP3A4 phenotyping using midazolam as a probe drug
timeFrame: Day 2: a blood sample will be collected after midazolam administration
measure: Genotyping the main SNPs on CYP2C9, CYP2D6, ABCB1 and SLCO1B1 genes
timeFrame: Day 1: a blood sample will be collected immediately after your check-in in the clinical research unit
measure: Transcriptomic analysis of liver extracellular vesicles
timeFrame: Day 1: a blood sample will be collected immediately after your check-in in the clinical research unit
measure: Transcriptomic analysis of intestine samples
timeFrame: Digestive biopsy collected in the second day of research protocol
Other outcomes:
Locations:
city: Orlando
country: United States
facility: University of Florida
state: Florida
Study officials:
affiliation: University of Sao Paulo
name: Wilson Salgado Junior, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Sao Paulo
name: Jose S dos Santos, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Florida
name: Natalia De Moraes, PhD
role: PRINCIPAL_INVESTIGATOR
References: