Assessment of Change in CYP3A Activity by Route of Administration Using Metabolic Markers in Healthy Male Volunteers

Study Overview
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Brief Summary
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The study objective is to evaluate and validate of endogenous markers for the assessment of change in CYP3A activity by route of administration in Korean healthy subjects using metabolomics. In addition, we aim to screen novel endogenous marker, which could determine the total or intestinal CYP activity.

Detailed Description
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This study is an open-label, one-sequence, three-period study. A total of 16 healthy male subjects will be enrolled. In period 1, subjects will be administered midazolam IV 1 mg, and co-administration of midazolam IV 1mg and grapefruit juice 500 mL. In period 2, subjects will be administered midazolam PO 5 mg, and co-administration of midazolam PO 5mg and grapefruit juice 500 mL. In period 3, subjects will be administered clarithromycin 500 mg for 3-days in b.i.d regimen prior to admission. Subjects will be administered midazolam IV 1mg and PO 5mg after admission.

Official Title
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Assessment of Change in CYP3A Activity by Route of Administration Using Metabolic Markers in Healthy Male Volunteers

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: Midazolam
* Drug: Clarithromycin
* Dietary Supplement: Grapefruit juice


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age: Between 19 to 50 years of age Weight: Within 17 - 28 of Body Mass Index (BMI) Subject who are reliable and willing to make themselves available during the study period, and subject who are willing to follow the study protocol, and give their written informed consent voluntarily. Exclusion Criteria: History of hypersensitive reaction to medication (midazolam, aspirin, NSAID, antibiotics, benzodiazepine, erythromycin, macrolide) 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 Subjects with evidence or a history of gastrointestinal disease (e.g, gastritis, Chron's disease) or with history of gastrointestinal surgery (except simple appendectomy or herniorrhaphy) that may affect assessment of PK characteristics of study drug Any of the following ECG abnormalities: QTcF > 450 msec History of apnea Subjects with genetic problems such as galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption Subject whose systolic blood pressure is over 150 mmHg or below 90 mmHg and diastolic blood pressure is over 100 mmHg or below 50 mmHg Subjects with a history of drug abuse or a positive urine screening for drug abuse Subjects who have participated in any other clinical trial within three months prior to study drug administration 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 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) Subjects who have donated a unit of whole blood within two months or blood components within one month prior to study drug administration Subjects who consume more than 21 units of alcohol per week (1 unit = 10 g of pure alcohol) or who are unable to abstain from drinking during the admission period Smokers (except for those who had quit for at least three months before the first administration of the IP) Subjects who consume or are unable to abstain from products containing grapefruit during study period Subjects who consume or are unable to abstain from products containing caffeine during study period Subjects who are positive for Hepatitis B, Hepatitis C, and HIV Subject who judged not eligible for study participation by investigator

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Interventional Model Description: An open-label, one-sequence, three-period study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CYP inhibition + IV/PO midazolam<br>Period 1: Administration of Midazolam (IV) on day 1, Co-administration of Midazolam (IV) and Grapefruit juice on day 2 Period 2: Administration of Midazolam (PO) on day 8, Co-administration of Midazolam (PO) and Grapefruit juice on day 9 Period 3: Self-administration of Clarithromycin (PO) bid regimen on day 12-14, Co-administration of Midazolam (IV) and Clarithromycin (PO) on day 15, Co-administration of Midazolam (PO) and Clarithromycin (PO) on day 16 | Drug: Midazolam<br>* Midazolam 5 mg PO, Midazolam 1 mg IV<br>Drug: Clarithromycin<br>* Clarithromycin 500 mg bid<br>Dietary Supplement: Grapefruit juice<br>* Grapefruit juice 500 mL<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the curve of midazolam (AUClast) | Pharmacokinetics of midazolam | Up to 12 hours after midazolam administration | 
| Metabolic ratio of steroids | endogenous metabolite profiles such as steroid (6beta-hydroxy-cortisol/cortisol, 6beta-hydroxy-cortisone/cortisone) | Up to 12 hours before/after midazolam administration | 
| Clearance (CL) of midazolam | Pharmacokinetics of midazolam | Up to 12 hours after midazolam administration |