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

Study Overview
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Brief Summary
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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
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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).

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

Conditions
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Healthy

Intervention / Treatment
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* Drug: Sildenafil
* Drug: Clarithromycin
* Drug: Itraconazole


Participation Criteria
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Eligibility Criteria
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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

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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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 |