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

NCT03366974 | Completed Phase 1 DMC

• 1 other identifier: CYP_IVPO
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Healthy Volunteers

Outcome Measures

Primary Outcomes (3)

• 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

Study Arms (1)

CYP inhibition + IV/PO midazolam

EXPERIMENTAL

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; Drug: Clarithromycin; Dietary Supplement: Grapefruit juice

Interventions

Midazolam DRUG

Midazolam 5 mg PO, Midazolam 1 mg IV

CYP inhibition + IV/PO midazolam

Clarithromycin DRUG

Clarithromycin 500 mg bid

CYP inhibition + IV/PO midazolam

Grapefruit juice DIETARY_SUPPLEMENT

Grapefruit juice 500 mL

CYP inhibition + IV/PO midazolam

Eligibility Criteria

• Age: 19 Years - 50 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Seoul National University Hospital: lead

Study Sites (1)

Seoul National University Hospital

Seoul, South Korea

Location

MeSH Terms

Interventions

Midazolam; Clarithromycin

Intervention Hierarchy (Ancestors)

Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Erythromycin; Macrolides; Polyketides; Lactones; Organic Chemicals

Study Officials

• Joo-Youn Cho

  Seoul National University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: An open-label, one-sequence, three-period study

Study Record Dates

• First Submitted: December 4, 2017
• First Posted: December 8, 2017
• Study Start: December 28, 2017
• Primary Completion: February 13, 2018
• Study Completion: December 12, 2018
• Last Updated: October 27, 2022

Record last verified: 2022-10

Locations

KR (1)