Evaluation of Metabolic Markers for the Prediction of DDI of Various CYP3A Substrates and Inhibitors

Phase 1

Completed

• Conditions: Healthy
• Interventions: Drug: Sildenafil; Drug: Clarithromycin; Drug: Itraconazole

• Registration Number: NCT02975037
• Lead Sponsor: Seoul National University Hospital

Brief Summary

Evaluation and validation of metabolic markers for the prediction of drug-drug interaction of various CYP3A4 substrates (sildenafil) and inhibitors (erythromycin/itraconazole) in healthy male subjects

Detailed Description

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 9P of Day -1. Urine collection is scheduled from 12 hours before sildenafil administration to 12 hours after administration. Subjects will be administered sildenafil (oral) around at 9A of Day 1. Subjects will perform scheduled procedures including clinical laboratory tests, electrocardiograms and blood samplings for pharmacokinetic, pharmacometabolomic and mRNA assessment.

Subjects will be administered either erythromycin or itraconazole (oral) around at 9A on Day 3 and 9A/9P on Day 4. Urine collection is scheduled from 0 hour to 12 hours after Day 3 erythromycin or itraconazole administration. Subjects will perform scheduled procedures including clinical laboratory tests, electrocardiograms and blood samplings for pharmacokinetic, pharmacometabolomic and mRNA assessment.

On Day 5, sildenafil will be administered with erythromycin or itraconazole around at 9A. Urine collection is scheduled from 12 hours before Day 5 drug administration to 12 hours after administration. Subjects will perform scheduled procedures. After subjects perform scheduled procedure, the study will be discharged (around 9A of Day 6).

Study participation was terminated on post-study visit (Day 12-14).

Study Timeline

• Study First Submitted: 2016-11-21
• Study First Submitted QC: 2016-11-22
• Study First Posted: 2016-11-29
• Study Start: 2017-02-06
• Primary Completion: 2017-03-04
• Study Completion: 2017-06-23
• Status Verified: 2022-10
• Last Update Submitted: 2022-10-25
• Last Update Posted: 2022-10-27

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Male
• Target Recruitment: 32

Inclusion Criteria

• Age: Between 19 to 50 years of age, inclusive
• Weight: within 17-28 of Body Mass Index (BMI)
• Subject who are reliable and willing to make themselves available during the study period.
• 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, itraconazole, 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
• 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)
• Participation in clinical trials of any drug within 3 months prior to the participation of the study
• Judged to be inappropriate for the study by the investigator

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
sildenafil+clarithromycin	Sildenafil	Sildenafil 25 mg PO (single dose); Clarithromycin 250 mg PO (3 doses); Sildenafil 25 mg PO + Clarithromycin 250 mg PO (single dose)
sildenafil+clarithromycin	Clarithromycin	Sildenafil 25 mg PO (single dose); Clarithromycin 250 mg PO (3 doses); Sildenafil 25 mg PO + Clarithromycin 250 mg PO (single dose)
sildenafil+itraconazole	Sildenafil	Sildenafil 25 mg PO (single dose); Itraconazole 100 mg PO (3 doses); Sildenafil 25 mg PO + Itraconazole 100 mg PO (single dose)
sildenafil+itraconazole	Itraconazole	Sildenafil 25 mg PO (single dose); Itraconazole 100 mg PO (3 doses); Sildenafil 25 mg PO + Itraconazole 100 mg PO (single dose)

Primary Outcome Measures

Name	Time	Method
Quantification of endogenous metabolites (plasma)	day 1 0h, day 3 0h, day 5 0h	Metabolomic profiles to predict CYP3A activity
Quantification of endogenous metabolites (urine)	day -1 12h~day 1 0h, day 1 0h~12h, day 3 0h~12h, day 4 12h~ day 5 0h, day 5 0h~12h	Metabolomic profiles to predict CYP3A activity

Secondary Outcome Measures

Name	Time	Method
Peak plasma concentration (Cmax)	day 1 0h (pre-dose), 10, 20, 30, 45 min, 1, 2, 3, 4, 6, 8, 12, 24h; day 3 0h (pre-dose), 10, 20, 30, 45 min, 1, 2, 3, 4, 6, 8, 12, 24h; day 5 0h (pre-dose), 10, 20, 30, 45 min, 1, 2, 3, 4, 6, 8, 12, 24h	Pharmacokinetics of CYP3A substrate and inhibitors
Area under the plasma concentration versus time curve (AUC)	day 1 0h (pre-dose), 10, 20, 30, 45 min, 1, 2, 3, 4, 6, 8, 12, 24h; day 3 0h (pre-dose), 10, 20, 30, 45 min, 1, 2, 3, 4, 6, 8, 12, 24h; day 5 0h (pre-dose), 10, 20, 30, 45 min, 1, 2, 3, 4, 6, 8, 12, 24h	Pharmacokinetics of CYP3A substrate and inhibitors

Trial Locations

Locations (1)

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