MedDRA version: 19.1 Level: LLT Classification code 10029885 Term: Obesity, unspecified System Organ Class: 100000004861
Conditions
Interventions
Trade Name: Klorzoxazon "DAK"
Pharmaceutical Form: Tablet
INN or Proposed INN: CHLORZOXAZONE
CAS Number: 95-25-0
Concentration unit: mg milligram(s)
Concentration type: range
Concentration number: 250
Sponsors
Bispebjerg Hospital
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: • Obese children (BMI = 99 % percentile) • Healthy non-obese children (BMI= 90 % percentile) • Age 11-18 years • Both genders (block stratified) • Postmenarche (females) • Written informed consent from both parents (age=65 years) no F.1.3.1 Number of subjects for this age range 0
Exclusion criteria
Exclusion criteria: • Acute or chronic Liver diseases • Other chronic diseases, except from allergic rhinitis, rash etc. • Intake of drugs known to induce of inhibit CYP2E1-, CYP3A4 and/or CYP1A2, including paracetamol, ciprofloxacin, azithromycin, ketoconazol, estradiol etc. • Citrus fruit • Alcohol intake within minimum 72 hours • Caffeine (Coca Cola©, coffee and tea) intake 48 h prior to administration of the caffeine-probe • Smoking 96 hours prior to administration of the caffeine-probe, screening test will be performed (nicotine metabolite: cotinine) • Kidney disease and dialysis • Pregnancy (test will be performed) • Known hypersensitivity to chlorzoxazone, midazolam or caffeine • vigorous exercise 24 hours before administration
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Research hypotheses: • CYP2E1- clearance is higher in obese children versus non-obese children • CYP3A4- clearance is lower in obese children versus non-obese children • CYP1A2- clearance is altered in obese children versus non-obese children Primary objectives: We want to investigate, whether the activity of some of the most important drug metabolizing enzymes, is altered in obese children versus non-obese children. Primary endpoints: These are the combined primary endpoints: Clearance of CYP2E1-, CYP1A2- and CYP3A4 substrates, defined by using well-tested probes (midazolam, chlorzoxazone and caffein). CYP2E1-, CYP1A2- and CYP3A4 clearance will be determined by following methods: • Chlorzoxazone multi-sample method (CYP2E1 activity) • Caffeine urinary metabolic ratio method (CYP1A2 activity) • Midazolam microdosing method (CYP3A4 activity) Cmax, Tmax , AUC, T1/2, and Vd will be defined blood samples collected at specific times and from urine collected for 24 hours. ;Secondary Objective: Secondary objective From and exploratory objective, we want to investigate whether an altered enzyme activity of CYP3A4, CYP2E1 and CYP1A2, is accociated with metabolic syndrome. Secondary endpoints: - Lipid profile - Inflammatory markers - Steatosis Markers of metabolic syndrome and steatosis: -Lipid profile: LDL, HDL, total cholesterol, triglyceride -Markers of insulin-resistance: Hba1C, Blood Glucose, Insuline -Inflammatory markers: TNFalfa, interleukin 6, leptin, adiponectin and CRP -Liver test: ASAT, ALAT, alkaline phosphatase, bilirubin, albumine and liver MR scanning (to verify steatosis) -24-hour blood pressure;Primary end point(s): These are the combined primary endpoints: Clearance of CYP2E1-, CYP1A2- and CYP3A4 substrates, defined by using well-tested probes (midazolam, chlorzoxazone and caffein). CYP2E1-, CYP1A2- and CYP3A4 will be determined by following methods: •Chlorzoxazone clearance (CYP2E1 activity) •Caffeine urinary metabolic ratio method ( | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): For Chlorzoxazone and midazolam: Cmax (maximum plasma concentration), Tmax (time to maximum plasma concentration), AUC (areal under the drug concentration /time curve), T1/2 (elimination half time) and Vd (volume of distribution) will be defined from blood samples taken at specific times. Lipid profile (LDL, HDL, total cholesterol, triglyceride), markers of insulin- resistance (Hba1C, Blood Glucose, insuline) ,inflammatory markers (TNFa, interleukin 6, leptin, adiponectin and CRP), liver tests (ASAT, ALAT, alkaline phosphatase, bilirubin, albumin), and creatinine .;Timepoint(s) of evaluation of this end point: Baseline blood samples, and after administration of chlorzoxazone: (t=10, 20, 30, 40, 50, 60, 90, 120 min and hourly for the next 4 hours) After administration of midazolam: Group 1 (25 obese and 25 non.obese trial participants): t=0, 2, 10, 20, 45, 90, 150, 210, 270, 360, 420, 480, 540 min. Group 2(25 obese and 25 non-obese trial participants): t=0, 5, 15, 30, 60, 120, 180, 240, 300, 360, 420, 480, 540 min. Urine will be collected completely for 24 hours post-dose. | — |
Countries
Denmark
Contacts
Public ContactHelle Holst
Klinisk Farmakologisk Afdeling, Bispebjerg Hospital
Outcome results
None listed