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

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.

Study Overview

• Status: Completed
• Conditions: Healthy Volunteers
• Intervention / Treatment: Drug: Midazolam; Drug: Clarithromycin; Dietary supplement: Grapefruit juice

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 1

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of
    • Seoul National University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years to 50 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: CYP inhibition + IV/PO midazolam; 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; Midazolam 5 mg PO, Midazolam 1 mg IV; Drug: Clarithromycin; Clarithromycin 500 mg bid; Dietary supplement: Grapefruit juice; Grapefruit juice 500 mL

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Seoul National University Hospital

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 28, 2017
• Primary Completion (ACTUAL): February 13, 2018
• Study Completion (ACTUAL): December 12, 2018

Study Registration Dates

• First Submitted: December 4, 2017
• First Submitted That Met QC Criteria: December 4, 2017
• First Posted (ACTUAL): December 8, 2017

Study Record Updates

• Last Update Posted (ACTUAL): October 27, 2022
• Last Update Submitted That Met QC Criteria: October 25, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Central Nervous System Depressants; Enzyme Inhibitors; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Anti-Bacterial Agents; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Protein Synthesis Inhibitors; Midazolam; Clarithromycin
• Other Study ID Numbers: CYP_IVPO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No