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

Evaluation and Validation of Metabolic Markers for the Prediction of Drug-drug Interaction of Various CYP3A4 Substrates and Inhibitors in Healthy Male Subjects

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

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Sildenafil; Drug: Clarithromycin; Drug: Itraconazole

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 Type: Interventional
• Enrollment (Actual): 32
• 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: 17 years to 48 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: sildenafil+clarithromycin; Sildenafil 25 mg PO (single dose); Clarithromycin 250 mg PO (3 doses); Sildenafil 25 mg PO + Clarithromycin 250 mg PO (single dose)	Drug: Sildenafil; sildenafil 25 mg PO; Other Names: VIAGRA TAB, Pfizer Pharmaceuticals Korea Limited, Korea; Drug: Clarithromycin; clarithromycin 250 mg PO; Other Names: CLARI TAB, Hanmi Pharm.Co.,Ltd., Korea
Experimental: sildenafil+itraconazole; Sildenafil 25 mg PO (single dose); Itraconazole 100 mg PO (3 doses); Sildenafil 25 mg PO + Itraconazole 100 mg PO (single dose)	Drug: Sildenafil; sildenafil 25 mg PO; Other Names: VIAGRA TAB, Pfizer Pharmaceuticals Korea Limited, Korea; Drug: Itraconazole; itraconazole 100 mg PO; Other Names: ITRA TAB, Hanmi Pharm.Co.,Ltd., Korea

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peak plasma concentration (Cmax)	Pharmacokinetics of CYP3A substrate and inhibitors	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
Area under the plasma concentration versus time curve (AUC)	Pharmacokinetics of CYP3A substrate and inhibitors	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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quantification of mRNA (whole blood)	Quantification of mRNA for CYP3A activity	day -1 12h, day 1 0, 12h, day 3 0, 12h, day 4 12h, day 5 0, 12h

Collaborators and Investigators

• Sponsor: Seoul National University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): February 6, 2017
• Primary Completion (Actual): March 4, 2017
• Study Completion (Actual): June 23, 2017

Study Registration Dates

• First Submitted: November 21, 2016
• First Submitted That Met QC Criteria: November 22, 2016
• First Posted (Estimate): November 29, 2016

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; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Anti-Infective Agents; Urological Agents; Enzyme Inhibitors; Hormones, Hormone Substitutes, and Hormone Antagonists; Anti-Bacterial Agents; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Protein Synthesis Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; Phosphodiesterase Inhibitors; 14-alpha Demethylase Inhibitors; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate; Clarithromycin; Itraconazole
• Other Study ID Numbers: CYP3A_DDI

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No