Ignite Creation Date:
2024-05-06 @ 3:27 AM
Last Modification Date:
2024-10-26 @ 11:33 AM
Study NCT ID:
NCT02291666
Status:
COMPLETED
Last Update Posted:
2019-07-23
First Post:
2014-10-30
Brief Title:
Evaluation of CYP450 Activities in Diabetic Patients vs Non-diabetic Subjects
Sponsor:
Centre hospitalier de lUniversité de Montréal CHUM
Organization:
Centre hospitalier de lUniversité de Montréal CHUM
Study Overview
Official Title:
Effects of Type 2 Diabetes on CYP450s Activities Intersubject Variability in Drug Metabolism
Status:
COMPLETED
Status Verified Date:
2017-07
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
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 andor 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 n126 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 CYP3A45 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
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 n126 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 CYP3A45 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
Detailed Description:
Patients with type 2 diabetes T2D require various therapeutic approaches diet exercise and drugs to ensure glycaemic control while minimizing the risk of hypoglycaemia T2D is also associated with vascular morbidities necessitating multiple drugs to prevent cardiovascular complications Clinical practice reveals that T2D patients show highly variable responses to different drugs Variable drug dosages and effects are observed for drugs such as clopidogrel warfarin cyclosporine and tacrolimus as well as for anti-hypertensive cholesterol lowering and antidiabetic drugs These observations strongly suggest that T2D modulates factors regulating drug disposition andor drug effects
The hypothesis underlying this proposal is T2D and its abnormalities alter the expression and activities of CYP450s involved in the disposition of drugs used to treat T2D and associated comorbidities
The overall objective of this project is to investigate the effects of T2D on the activity of several CYP450 isozymes Primary objective To compare CYP450 activities between diabetic and non-diabetic subjects following a single oral administration of a cocktail of CYP450 probe drugs The secondary objective To evaluate and compare CYP450 activities according to the glycemic control T2D patients with good glycemic control T2D patients with poor glycemic control and non-diabetic healthy subjects
Study design Patients n126 will be recruited to constitute 3 groups Group I 42 confirmed T2D with HbA1c 70 Group II 42 patients with poor glycemic control HbA1c70 and Group III 42 sexed-matched non-T2D healthy subjects This design will allow us to compare CYP450 activities between T2D patients with good glycemic control T2D patients with poor glycemic control and non-diabetic healthy subjects Participants will be 18 years old with a body weight index 35 and be non-smokers 3 months Subjects will be recruited at the CHUM outpatient clinic The T2D diagnosis will be established according to the Canadian clinical guidelines After an overnight fast participants will be admitted to the CRCHUMs Clinical Research Unit they will be not hospitalized Subjects will receive the CRCHUM-MT cocktail 100mg caffeine 100mg bupropion 250mg tolbutamide 20mg omeprazole 30mg dextromethorphan and 2mg midazolam to phenotype for CYP1A2 2B6 2C9 2C19 2B6 2D6 and 3A45 respectively Serial blood samples will be drawn and urine collected over 8 hours following drug administration At the end of study day subjects will be discharged from the CRCHUMs Clinical Research Unit and an oral 250mg dose of chlorzoxazone CYP2E1 will be given and urine collected overnight for 12 hours
A blood sample will be taken for pharmacogenetic analysis for relevant drug metabolizing enzymes Additional blood samples will be collected just before the administration of the cocktail to measure insulin glycaemia and HbA1c levels biomarkers and inflammatory markers
The subjects will be instructed not to take any medication caffeine or theobromine containing products on the morning of study day Their regular medication will be administered 4 hours after the administration of the cocktail if indicated The subjects in whom our probe marker drugs are used daily will still be enrolled as metabolic ratios and will be determined to establish CYP450 activities
Pharmacokinetic parameters such as oral clearance metabolic clearance and renal clearance will be determined by noncompartmental analysis Metabolic ratios will be calculated and compared between three groups of subjects
The hypothesis underlying this proposal is T2D and its abnormalities alter the expression and activities of CYP450s involved in the disposition of drugs used to treat T2D and associated comorbidities
The overall objective of this project is to investigate the effects of T2D on the activity of several CYP450 isozymes Primary objective To compare CYP450 activities between diabetic and non-diabetic subjects following a single oral administration of a cocktail of CYP450 probe drugs The secondary objective To evaluate and compare CYP450 activities according to the glycemic control T2D patients with good glycemic control T2D patients with poor glycemic control and non-diabetic healthy subjects
Study design Patients n126 will be recruited to constitute 3 groups Group I 42 confirmed T2D with HbA1c 70 Group II 42 patients with poor glycemic control HbA1c70 and Group III 42 sexed-matched non-T2D healthy subjects This design will allow us to compare CYP450 activities between T2D patients with good glycemic control T2D patients with poor glycemic control and non-diabetic healthy subjects Participants will be 18 years old with a body weight index 35 and be non-smokers 3 months Subjects will be recruited at the CHUM outpatient clinic The T2D diagnosis will be established according to the Canadian clinical guidelines After an overnight fast participants will be admitted to the CRCHUMs Clinical Research Unit they will be not hospitalized Subjects will receive the CRCHUM-MT cocktail 100mg caffeine 100mg bupropion 250mg tolbutamide 20mg omeprazole 30mg dextromethorphan and 2mg midazolam to phenotype for CYP1A2 2B6 2C9 2C19 2B6 2D6 and 3A45 respectively Serial blood samples will be drawn and urine collected over 8 hours following drug administration At the end of study day subjects will be discharged from the CRCHUMs Clinical Research Unit and an oral 250mg dose of chlorzoxazone CYP2E1 will be given and urine collected overnight for 12 hours
A blood sample will be taken for pharmacogenetic analysis for relevant drug metabolizing enzymes Additional blood samples will be collected just before the administration of the cocktail to measure insulin glycaemia and HbA1c levels biomarkers and inflammatory markers
The subjects will be instructed not to take any medication caffeine or theobromine containing products on the morning of study day Their regular medication will be administered 4 hours after the administration of the cocktail if indicated The subjects in whom our probe marker drugs are used daily will still be enrolled as metabolic ratios and will be determined to establish CYP450 activities
Pharmacokinetic parameters such as oral clearance metabolic clearance and renal clearance will be determined by noncompartmental analysis Metabolic ratios will be calculated and compared between three groups of subjects
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None