Identification and Evaluation of Endogenous Markers for the Assessment of CYP3A Activity

• ClinicalTrials.gov Identifier: NCT01760642
• Recruitment Status: Completed
• First Posted: January 4, 2013
• Last Update Posted: May 26, 2014
• Sponsor: Seoul National University Hospital
• Information provided by (Responsible Party): Joo-Youn Cho, Seoul National University Hospital

Study Description

Brief Summary:

Identification and evaluation of endogenous markers for the assessment of CYP3A activity in female subjects using metabolomics

Condition or disease	Intervention/treatment	Phase
Healthy	Drug: Midazolam; Drug: Ketoconazole; Drug: Rifampicin	Phase 1

Detailed Description:

Eligibility for participation of this study will be determined from demographic information, medical history, physical examination, electrocardiogram(ECG) and clinical laboratory tests within 3 weeks before study drug administration. Subjects suitable for this study will be admitted to the Clinical Trials Center, Seoul National University Hospital on the day before dosing, and they will be overnight-fasted from 9 p.m. of Day -1. Urine collection is scheduled from 24 hours before midazolam administration to 24 hours after administration. Subjects will be dosed midazolam by intravenous around at 9 a.m. of Day 1. Subjects will perform scheduled procedures including clinical laboratory tests, electrocardiograms and pharmacokinetic samplings. Subjects will be discharged on Day 2 and visit the Clinical Trials Center for period 2, ketoconazole administration. After 3 days of ketoconazole administration, midazolam will be dosed with ketoconazole on Day 4 of period 2. Subjects will perform scheduled procedure and on period 3 rifampicin will be dosed for 9 days and on Day 10 of period 3 midazolam will be dosed with rifampicin. After subjects perform scheduled procedure, the study will be terminated 6-8 days after the end of period 3.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 16 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Identification and Evaluation of Endogenous Markers for the Assessment of CYP3A Activity in Female Subjects Using Metabolomics
• Study Start Date: December 2012
• Actual Primary Completion Date: September 2013
• Actual Study Completion Date: September 2013

Arms and Interventions

Arm	Intervention/treatment
Experimental: Midazolam; period 1: midazolam 1 mg IV single dose administration. period 2: midazolam 1 mg IV single dose after ketoconazole 400 mg oral dosing for 3 days. period 3: midazolam 2.5 mg IV single dose after rifampicin 600 mg oral dosing for 10 days.	Drug: Midazolam; Midazolam 3 mg IV; Other Name: Midazolam (Bukwang Pharm.Co., Ltd.); Drug: Ketoconazole; ketoconazole 400 mg PO; Other Name: Kaszole (Skynewpharm Inc.); Drug: Rifampicin; Rifampicin 600 mg PO; Other Name: Rifampin (Yuhan Corp.)

Outcome Measures

Primary Outcome Measures :

1. Metabolomic profile [ Time Frame: -24--12h, -12-0h of every midazolam dosing ]
   endogenous metabolite profiles such as steroid

Secondary Outcome Measures :

1. Pharmacokinetics [ Time Frame: 0h, 10m, 20m, 30m, 45m, 1h, 2h, 3h, 4h, 6h, 8h, 12h, 24h of every midazolam dosing ]
   Cmax, AUClast of midazolam

Eligibility Criteria

• Ages Eligible for Study: 20 Years to 50 Years (Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• Age: Between 20 to 50 years of age, inclusive
• Weight: Between 45 to 95 kg, within 17 - 28 of Body Mass Index
• Menstruation cycle between 21 to 35 without contraceptive
• Subject who agree contraception during the study
• Subject who are reliable and willing to make themselves available during the study period, are willing to follow the study protocol, and give their written informed consent voluntarily

Exclusion Criteria:

• History of hypersensitive reaction to medication (midazolam, ketoconazole, rifampicin)
• History of significant clinical illness needs medical caution, including cardiovascular, immunologic, hematologic, neuropsychiatric, respiratory, gastrointestinal, hepatic, or renal disease or other chronic disease history or evidence of drug abuse
• A subject whose lab test results are as follows; Liver function test (AST, ALT, GGT, ALP, LDH, Total bilirubin) > 1.25 X upper limit of reference range
• A subject whose SBP is over 140 mmHg or below 90 mmHg and DBP is over 100 mmHg or below 50 mmHg
• Presence or history of drug abuse or positive result in urine drug screening test
• Blood donation during 2 months or apheresis during 1 month before the study
• Use any prescriptive medication, Korean traditional medication not considered acceptable by the clinical investigator during the last 14 days period before first dosing, or use any OTC medication not considered acceptable by the clinical investigator during the last 7 days period before first dosing (if used medication is considered acceptable by investigator, patients can be included)
• Use of alcohol over 21 units/weeks
• Smoker who smoke more than 10 cigarettes per day
• Participation in clinical trials of any drug within 60 days prior to the participation of the study
• Use of grapefruit juice within 1 week before first dose
• Use of caffeine drink within 3 days before first dose
• Subject pregnant or breast-feeding
• Judged to be inappropriate for the study by the investigator

Contacts and Locations

Locations

Korea, Republic of

Seoul National Universtiy Hospital

Seoul, Korea, Republic of, 110-744

Sponsors and Collaborators

Seoul National University Hospital

Investigators

• Principal Investigator: Joo-Youn Cho, PhD; Seoul National University Hospital

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Shin KH, Ahn LY, Choi MH, Moon JY, Lee J, Jang IJ, Yu KS, Cho JY. Urinary 6β-Hydroxycortisol/Cortisol Ratio Most Highly Correlates With Midazolam Clearance Under Hepatic CYP3A Inhibition and Induction in Females: A Pharmacometabolomics Approach. AAPS J. 2016 Sep;18(5):1254-1261. doi: 10.1208/s12248-016-9941-y. Epub 2016 Jun 17.

• Responsible Party: Joo-Youn Cho, Professor, Seoul National University Hospital
• ClinicalTrials.gov Identifier: NCT01760642
• Other Study ID Numbers: CYP_metabolomics
• First Posted: January 4, 2013
• Last Update Posted: May 26, 2014
• Last Verified: May 2014

Keywords provided by Joo-Youn Cho, Seoul National University Hospital:

metabolite profiles; pharmacokinetics; CYP3A; metabolomics

Additional relevant MeSH terms:

Rifampin; Ketoconazole; Midazolam; Adjuvants, Anesthesia; Hypnotics and Sedatives; Central Nervous System Depressants; Physiological Effects of Drugs; Anti-Anxiety Agents; Tranquilizing Agents; Psychotropic Drugs; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; GABA Modulators; GABA Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antibiotics, Antitubercular; Antitubercular Agents; Anti-Bacterial Agents; Anti-Infective Agents; Leprostatic Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP2C8 Inducers; Cytochrome P-450 CYP2C19 Inducers; Cytochrome P-450 CYP2C9 Inducers; Cytochrome P-450 CYP3A Inducers