A Drug-drug Interaction Study to Evaluate the Effect of Rifampicin and Febuxostat on the Pharmacokinetics of Methotrexate in Healthy Subjects

Study Overview
=================
Brief Summary
-----------------
To investigate the effect of rifampicin and febuxostat on pharmacokinetics of methotrexate in healthy volunteers

Official Title
-----------------
A Drug-drug Interaction Study to Evaluate the Effect of Rifampicin and Febuxostat on the Pharmacokinetics of Methotrexate in Healthy Subjects

Conditions
-----------------
Drug Interaction

Intervention / Treatment
-----------------
* Drug: Methotrexate Sodium
* Drug: Rifampicin Sodium
* Drug: Febuxostat Tablets


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age between 19 to 50, healthy male subjects (at screening) Body weight between 50.0 kg - 90.0 kg, BMI between 18.0 - 30.0 kg/m2 Subject who totally understand the progress of this clinical trials, make decision by his free will, and signed a consent form to follow the progress Exclusion Criteria: Subject who has a past or present history of any diseases (eg. liver, kidney, neurology, immunology, pulmonary, endocrine, hematology, oncology, cardiology, mental disorder) Subject who had GI tract disease (Crohn's disease, ulcer, acute or chronic pancreatitis) or surgery (appendectomy, hernioplasty are excluded) Serum AST(SGOT), ALT(SGPT), total bilirubin >1.5 times upper limit of normal range, MDRD eGFR < 60mL/min/1.73m2, WBC count < 3,500 /uL, SBP < 90 mmHg or > 150 mmHg, DBP < 50 mmHg or >100 mmHg Subject who had galactose intolerance, Lapplactase deficiency or glucose-galactose malabsorption Subject who had received drugs inhibiting or inducing metabolic enzymes/transporters such as barbiturates, statins, digoxin in 3 months Subject who had taken St.John's wort and food including grapefruit in 2 weeks Smoking in 3 months Subject who had whole blood donation in 2 months, or component blood donation in 1 month or transfusion in 1 month currently

Ages Eligible for Study
-----------------
Minimum Age: 19 Years
Maximum Age: 45 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Methotrexate<br> | Drug: Methotrexate Sodium<br>* Methotrexate oral administration alone<br>|
| Experimental: Methotrexate + Rifampicin<br>Methotrexate + Rifampicin | Drug: Methotrexate Sodium<br>* Methotrexate oral administration alone<br>Drug: Rifampicin Sodium<br>* Co-administration of methotrexate and rifampicin<br>|
| Experimental: Methotrexate + Febuxostat<br>Methotrexate + Febuxostat | Drug: Methotrexate Sodium<br>* Methotrexate oral administration alone<br>Drug: Febuxostat Tablets<br>* Co-administration of methotrexate and febuxostat<br>|
| Experimental: Methotrexate + Rifampicin + Febuxostat<br>Methotrexate + Rifampicin + Febuxostat | Drug: Methotrexate Sodium<br>* Methotrexate oral administration alone<br>Drug: Rifampicin Sodium<br>* Co-administration of methotrexate and rifampicin<br>Drug: Febuxostat Tablets<br>* Co-administration of methotrexate and febuxostat<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compare Cmax of methotrexate | Compare the maximum concentration (Cmax), area under the plasma concentration-time curve to last measurable time point (AUClast) and area under the plasma concentration-time curve from 0 hours to infinite time (AUCinf) of methotrexate | pre-dose (0h), 0, 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 24 h post-dose (Period 1, 2, 3, 4 Day 1) | 
| Compare AUClast of methotrexate | Compare the area under the plasma concentration-time curve to from 0 to last measurable time point (AUClast) of methotrexate | pre-dose (0h), 0, 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 24 h post-dose (Period 1, 2, 3, 4 Day 1) | 
| Compare AUCinf of methotrexate | Compare area under the plasma concentration-time curve from 0 hours to infinite time (AUCinf) of methotrexate | pre-dose (0h), 0, 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 24 h post-dose (Period 1, 2, 3, 4 Day 1) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compare Cmax of 7-hydroxy methotrexate | Compare the maximum concentration (Cmax) of 7-hydroxy methotrexate | pre-dose (0h), 0, 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 24 h post-dose (Period 1, 2, 3, 4 Day 1) | 
| Compare AUClast of 7-hydroxy methotrexate | Compare area under the plasma concentration-time curve to last measurable time point (AUClast) of 7-hydroxy methotrexate | pre-dose (0h), 0, 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 24 h post-dose (Period 1, 2, 3, 4 Day 1) | 
| Compare AUCinf of 7-hydroxy methotrexate | Compare area under the plasma concentration-time curve from 0 hours to infinite time (AUCinf) of 7-hydroxy methotrexate | pre-dose (0h), 0, 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 24 h post-dose (Period 1, 2, 3, 4 Day 1) |