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

Phase 1

Completed

• Conditions: Healthy
• Interventions: Drug: Midazolam; Drug: Ketoconazole; Drug: Rifampicin

• Registration Number: NCT01760642
• Lead Sponsor: Seoul National University Hospital

Brief Summary

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

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 Timeline

• Study Start: 2012-12
• Study First Submitted: 2012-12-26
• Study First Submitted QC: 2013-01-01
• Study First Posted: 2013-01-04
• Primary Completion: 2013-09
• Study Completion: 2013-09
• Status Verified: 2014-05
• Last Update Submitted: 2014-05-23
• Last Update Posted: 2014-05-26

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Female
• Target Recruitment: 16

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Midazolam	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.
Midazolam	Ketoconazole	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.
Midazolam	Rifampicin	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.

Primary Outcome Measures

Name	Time	Method
Metabolomic profile	-24--12h, -12-0h of every midazolam dosing	endogenous metabolite profiles such as steroid

Secondary Outcome Measures

Name	Time	Method
Pharmacokinetics	0h, 10m, 20m, 30m, 45m, 1h, 2h, 3h, 4h, 6h, 8h, 12h, 24h of every midazolam dosing	Cmax, AUClast of midazolam

Trial Locations

Locations (1)

Seoul National Universtiy Hospital; 🇰🇷 Seoul, Korea, Republic of