Co-Administration Of Methotrexate And CP-690,550

Study Overview
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Brief Summary
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This study was designed to estimate the effects of methotrexate (MTX) on the pharmacokinetics (PK) of CP-690,550 when administered to subjects with rheumatoid arthritis (RA), to estimate the effects of CP-690,550 on the PK of MTX and to evaluate the short-term safety and tolerability of co-administration of CP-690,550 and MTX.

Official Title
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A Phase 1, Open Label Study Of The Pharmacokinetics Of Multiple Doses Of Oral CP-690,550 And Single Doses Of Oral Methotrexate In Rheumatoid Arthritis Subjects

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: CP-690,550 (tofacitinib)
* Drug: Methotrexate (MTX)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults diagnosed with moderate to severe RA (Rheumatoid Arthritis) Diagnosis of RA based on the American College of Rheumatology 1987 revised criteria. Treatment with an oral stable weekly dose of Methotrexate (MTX) (15-25 mg/week, administered as a single dose [SD]) for a minimum of 4 doses (4 weeks) Exclusion Criteria: Blood dyscrasias including confirmed: Hemoglobin <9 g/dL or Hematocrit <30%; White blood cell count <3.0 x 109/L; Absolute neutrophil count <1.2 x 109/L; Platelet count <100 x 109/L Evidence or history of clinically significant infections within the past 6 months (eg, those requiring hospitalization, requiring parenteral antimicrobial therapy, or those with recurrent oral or genital herpes, recurrent herpes zoster, or any infection otherwise judged by the investigator to have the potential for exacerbation by participation in the trial. Total bilirubin, AST (aspartate aminotransferase) or ALT (alanine aminotransferase) more than 1.2 times the upper limit of normal at the Screening visit, or a history of clinically significant elevated liver function tests (LFTs) while on current MTX dose or chronic liver disease, recent or active hepatitis.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CP-690,550 (tofacitinib) 30 mg q12h<br>Individual dose of methotrexate with the addition of CP-690,550 30 mg q12h | Drug: CP-690,550 (tofacitinib)<br>* CP-690,550 30 mg q12h for 5 days<br>Drug: Methotrexate (MTX)<br>* individual dose of methotrexate (stably dosed)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve From Time Zero to 12 Hours [AUC (0-12)] for CP-690,550 | AUC (0-12)= area under the plasma concentration time-curve from time zero (pre-dose) to 12 hours (0-12). | 0 (pre-dose), 0.25, 0.5, 1, 2, 3, 4, 8 and 12 hours post-dose on Day 6 and Day 7 | 
| Maximum Observed Plasma Concentration (Cmax) for CP-690,550 |  | 0 (pre-dose), 0.25, 0.5, 1, 2, 3, 4, 8 and 12 hours post-dose on Day 6 and Day 7 | 
| Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) for Methotrexate (MTX) | Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). | 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24 and 48 hours post-dose on Day 1 and Day 7 | 
| Maximum Observed Plasma Concentration (Cmax) for Methotrexate (MTX) |  | 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8,12, 24 and 48 hours post-dose on Day 1 and Day 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) for CP-690,550 |  | 0 (pre-dose), 0.25, 0.5, 1, 2, 3, 4, 8 and 12 hours post-dose on Day 6 and Day 7 | 
| Plasma Decay Half-Life (t1/2) for CP-690,550 | Plasma decay half-life is the time measured for the plasma concentration of CP-690,550 to decrease by one half. | 0 (pre-dose), 0.25, 0.5, 1, 2, 3, 4, 8 and 12 hours post-dose on Day 6 and Day 7 | 
| Apparent Oral Clearance (CL/F) for CP-690,550 | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population PK modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. | 0 (pre-dose), 0.25, 0.5, 1, 2, 3, 4, 8 and 12 hours post-dose on Day 6 and Day 7 | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) for Methotrexate (MTX) |  | 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8 ,12, 24 and 48 hours post-dose on Day 1 and Day 7 | 
| Plasma Decay Half-Life (t1/2) for Methotrexate (MTX) | Plasma decay half-life is the time measured for the plasma concentration of MTX to decrease by one half. | 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8 , 12, 24 and 48 hours post-dose on Day 1 and Day 7 | 
| Apparent Oral Clearance (CL/F) for Methotrexate (MTX) | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population PK modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. | 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8 , 12, 24 and 48 hours post-dose on Day 1 and Day 7 | 
| Total Amount of Unchanged Drug Excreted in the Urine From Time Zero to 12 Hours (Ae[0-12]) for CP-690,550 |  | 0 (pre-dose) through 12 hours post-dose on Day 6 and Day 7 | 
| Renal Clearance (CL R) for CP-690,550 |  | 0 (pre-dose) through 24 hours post-dose on Day 6 and Day 7 | 
| Total Amount of Unchanged Drug Excreted in the Urine From Time Zero to 24 Hours (Ae[0-24]) for Methotrexate (MTX) |  | 0 (pre-dose) through 24 hours post-dose on Day 1 and Day 7 | 
| Renal Clearance (CL R) for Methotrexate (MTX) |  | 0 (pre-dose) through 24 hours post-dose on Day 1 and Day 7 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pharmacokinetics, oral JAK inhibitor, methotrexate (MTX), rheumatoid arthritis (RA)