Evaluation of CYP450 Activities in Diabetic Patients vs. Non-diabetic Subjects

NCT02291666 | Completed Phase 4 DMC

• 1 other identifier: CE 14.066
• Study Type: interventional
• Target: 73
• Locations: 1 country
• Sites: 1

Brief Summary

Type 2 diabetes (T2D) could modulate CYP450 activities involved in drug-metabolism and cardiovascular homeostasis. We propose to carry out, for the first time, a comprehensive characterization of the effects of T2D on the expression and activity of major CYP450s. In our studies, patients with T2D will be studied since hyperglycaemia and/or hyperinsulinemia are believed to modulate CYP450s. This vicious cycle puts patients at risk of micro- and macro-vascular complications and inadequately controlled T2D due to high intersubject variability in drug disposition and action. Characterization of the effects of T2D on drug metabolism capacity will be performed using a cocktail of CYP450 probe drugs. CYP450 phenotype will be determined in 3 groups of patients (n=126 patients): 1) 42 T2D patients with good glycemic control; 2) 42 T2D patients with poor glycemic control; and 3) 42 non-T2D healthy subjects following a single oral administration of a cocktail of CYP450 probe drugs. Subjects will receive the CRCHUM-MT cocktail consisting of caffeine (CYP1A2), bupropion (CYP2B6), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), midazolam (CYP3A4/5) and chlorxozaxone (which will be administered separately) (CYP2E1). Serial blood samples will be drawn and urine collected. Metabolic ratios will be calculated and compared between three groups of subjects. Other co-variables to be studied include T2D biomarkers at baseline (glucose, insulin, HbA1c), medications, genetic polymorphisms and inflammatory markers. Our cocktail probe drug approach should allow us to demonstrate the effects of T2D on the activity of major CYP450s. Moreover, this project will indicate to us whether glycemic control should be considered as a covariate of intersubject variability in drug metabolism capacity.

Conditions

Type 2 Diabetes

Keywords

Cytochromes p450; drug metabolism; pharmacokinetics; diabetes; probe markers

Outcome Measures

Primary Outcomes (1)

• Metabolic ratio

  The metabolite/probe-drug (parent compound) ratio will be used as a metabolic index of CYP activity.

  12 hours

Secondary Outcomes (2)

• Oral clearance

  12 hours

• Renal clearance

  12 hours

Study Arms (3)

T2D patients with A1C ≤7.0

EXPERIMENTAL

CRCHUM-MT cocktail; a single oral dose of the CRCHUM-MT cocktail will be administered; 100mg caffeine, 75mg bupropion, 150mg tolbutamide, 20mg omeprazole, 30mg dextromethorphan, 2mg midazolam and at night, one oral 250mg dose of chlorzoxazone will be taken separately.

Drug: CRCHUM-MT cocktail

T2D patients with A1C>7.0

EXPERIMENTAL

CRCHUM-MT cocktail; a single oral dose of the CRCHUM-MT cocktail will be administered; 100mg caffeine, 75mg bupropion, 150mg tolbutamide, 20mg omeprazole, 30mg dextromethorphan, 2mg midazolam and at night, one oral 250mg dose of chlorzoxazone will be taken separately.

Drug: CRCHUM-MT cocktail

Non T2D subjects

ACTIVE COMPARATOR

CRCHUM-MT cocktail; a single oral dose of the CRCHUM-MT cocktail will be administered; 100mg caffeine, 75mg bupropion, 150mg tolbutamide, 20mg omeprazole, 30mg dextromethorphan, 2mg midazolam and at night, one oral 250mg dose of chlorzoxazone will be taken separately.

Drug: CRCHUM-MT cocktail

Interventions

CRCHUM-MT cocktail DRUG

Also known as: omeprazole, Losec, caffeine, Wake-up, bupropion, Wellbutrin, Zyban, dextromethorphan, midazolam, tolbutamide, chlorzoxazone, Acetazone

Non T2D subjects; T2D patients with A1C ≤7.0; T2D patients with A1C>7.0

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants will be ≥18 years old
• Body weight index ≤35,
• Non-smokers (\>3 months)
• Patients with type 2 diabetes and good glycemic control (A1C\<7) or poor glycemic control (A1C\>7.0) and healthy non-diabetic subjects will be eligible.

You may not qualify if:

• Subjects with estimated glomerular filtration (MDRD) \<50mL/min/1.73m2
• ALT and AST 3 times above the upper limit of normal
• Organ transplant recipient, inflammatory illnesses (i.e., polyarthritis, severe cirrhosis, infectious diseases, heart failure, HIV, hepatitis)
• Previous history of or an active cancer (except non-melanoma skin cancer)
• Uncontrolled thyroid functions
• Pregnant
• History of drug or alcohol abuse
• Subjects with a history of or current inflammatory bowel diseases including ulcerous colitis and Crohn's disease, and bariatric surgery
• Drugs known to modulate CYP450 activities, subject taking one of the following therapies will be excluded: antibiotics, antivirals, anticancers, CYP450 inducers (carbamazepine, phenobarbital, phenytoin, rifampin, St-John's wort), CYP450 inhibitors (amiodarone, fluvoxamine, fluoxetine, verapamil), immunosuppressors, warfarin, INFs, antibodies or grapefruit juice (\<2-4 weeks) , CYP450 drugs with strong affinity for the selected isoform and with a long half-life, CYP450 mechanism-based inhibitors or an investigational drug
• Intolerance or hypersensitivity to probe drugs in the CRCHUM-MT cocktail or chlorzoxazone/acetaminophen

Sponsors & Collaborators

• Centre hospitalier de l'Université de Montréal (CHUM): lead
• Canadian Institutes of Health Research (CIHR): collaborator

Study Sites (1)

Centre hospitalier de l'Université de Montréal (CHUM)

Montreal, Quebec, H2X0A9, Canada

Location

Related Publications (2)

• Gravel S, Chiasson JL, Turgeon J, Grangeon A, Michaud V. Modulation of CYP450 Activities in Patients With Type 2 Diabetes. Clin Pharmacol Ther. 2019 Dec;106(6):1280-1289. doi: 10.1002/cpt.1496. Epub 2019 Jul 9.

  PMID: 31099895 DERIVED

• Gravel S, Chiasson JL, Dallaire S, Turgeon J, Michaud V. Evaluating the impact of type 2 diabetes mellitus on CYP450 metabolic activities: protocol for a case-control pharmacokinetic study. BMJ Open. 2018 Feb 8;8(2):e020922. doi: 10.1136/bmjopen-2017-020922.

  PMID: 29439084 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 2; Diabetes Mellitus

Interventions

Omeprazole; Caffeine; Wuc protein, Drosophila; Bupropion; Dextromethorphan; Midazolam; Tolbutamide; Chlorzoxazone

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

2-Pyridinylmethylsulfinylbenzimidazoles; Sulfoxides; Sulfur Compounds; Organic Chemicals; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Xanthines; Alkaloids; Purinones; Purines; Propiophenones; Ketones; Morphinans; Opiate Alkaloids; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds; Benzodiazepines; Benzazepines; Benzenesulfonamides; Sulfonamides; Amides; Sulfonylurea Compounds; Urea; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sulfones; Benzoxazoles

Study Officials

• Veronique Michaud, BPharm, PhD

  Centre de recherche du Centre Hospitalier de l'université de Montréal (CHUM)

  PRINCIPAL INVESTIGATOR

• Jean-Louis Chiasson, MD

  Centre hospitalier de l'Université de Montréal (CHUM)

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NON RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 30, 2014
• First Posted: November 14, 2014
• Study Start: April 1, 2015
• Primary Completion: July 1, 2019
• Study Completion: July 1, 2019
• Last Updated: July 23, 2019

Record last verified: 2017-07

Locations

CA (1)