Study to Investigate the Effect of BMS-986142 on the Pharmacokinetics (PK) of Methotrexate and Probe Substrate Cocktail in Healthy Patients

Study Overview
=================
Brief Summary
-----------------
To study the Pharmacokinetics (PK) parameters of montelukast, flurbiprofen, midazolam, digoxin, pravastatin, and MTX when coadministered with BMS-986142.

Official Title
-----------------
Effects of BMS-986142 on the Single-dose Pharmacokinetics of Methotrexate and Probe Substrates Montelukast (CYP2C8), Flurbiprofen (CYP2C9), Midazolam (CYP3A4), Digoxin (P-gp), and Pravastatin (OATP1B1) in Healthy Subjects

Conditions
-----------------
Rheumatoid Arthritis

Intervention / Treatment
-----------------
* Drug: Montelukast, Flurbiprofen, Midazolam, Digoxin, Pravastatin and BMS-986142
* Drug: Methotrexate, Leucovorin and BMS-986142


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Groups 1 and 2: Written informed consent from all subjects. Body mass index (BMI) of 18.0 to 32.0 kg/m2, inclusive Non-smokers. Normal renal function at screening as evidenced by an estimated glomerular filtration rate (GFR) of > 90 mL/min/1.73 m2 . Subject reenrollment. Males who are sexually active with women of childbearing potential (WOCBP) must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug plus 5 half-lives of BMS-986142. Male subjects must be willing to refrain from sperm donation during the entire study plus 5 half-lives of BMS-986142. Group 1 only: Healthy male and female (not of childbearing potential) subjects as determined by medical history, and clinical assessments. Women must have documented proof that they are not of childbearing potential and must not be breast feeding. Group 2 only: 1. Healthy male subjects as determined by medical history, and clinical assessments. Exclusion Criteria: Administration of live vaccine including polio vaccine during the course of the study, 12 weeks prior to the first dose of study drug, or 30 days after the last dose of study drug. Active tuberculosis (TB) requiring treatment within the previous 3 years. History of herpes zoster. Subjects who have experienced recent infection, upper respiratory infection,.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
-----------------
All

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

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

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1<br>Montelukast, Flurbiprofen, Midazolam, Digoxin, Pravastatin and BMS-986142 | Drug: Montelukast, Flurbiprofen, Midazolam, Digoxin, Pravastatin and BMS-986142<br>* Montelukast 10-mg tablet: On Days 1 and 8,Single oral dose Flurbiprofen 50-mg tablet: On Days 1 and 8,Single oral dose Midazolam syrup 2.5 mL × 2 mg/mL (5 mg): On Days 1 and 8,Single oral dose Digoxin (Lanoxin®) 0.25 mg tablet: On Days 1 and 8,Single oral dose Pravastatin 40-mg tablet: On Days 1 and 8,Single oral dose BMS-986142: On Days 6 through 12.<br>|
| Experimental: Group 2<br>Methotrexate,Leucovorin and BMS-986142 | Drug: Methotrexate, Leucovorin and BMS-986142<br>* Methotrexate (MTX) single oral dose of 3 × 2.5-mg tablet (Days 1 and 8) Leucovorin single oral dose of 15-mg tablet (Days 2 and 9; 24 hours after MTX administration) BMS-986142 on Days 6 through 10.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum observed plasma concentration (Cmax) |  | Days 1 through 10 | 
| Area under the plasma concentration-time curve from time zero to the time of last quantifiable concentration, AUC(0-T) |  | Days 1 through 10 | 
| Area under the plasma concentration-time curve from time zero extrapolated to infinite time, AUC(INF) |  | Days 1 through 10 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time of maximum observed plasma concentration (Tmax) |  | Days 1 through 10 | 
| Terminal plasma half-life (T-half) |  | Days 1 through 10 | 
| Apparent total body clearance (parents only), CLT/F |  | Days 1 through 10 | 
| Ratio of metabolite Cmax to parent Cmax, corrected for molecular weight |  | Days 1 through 10 | 
| Ratio of metabolite AUC(0-T) to parent AUC(0-T), corrected for molecular weight |  | Days 1 through 10 | 
| Ratio of metabolite AUC(INF) to parent AUC(INF), corrected for molecular weight |  | Days 1 through 10 | 
| Trough observed plasma concentration (For BMS-986142 only) |  | Days 1 through 10 |