Co-Administration Of Methotrexate And CP-690,550

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

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.

Study Overview

• Status: Completed
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Drug: CP-690,550 (tofacitinib); Drug: Methotrexate (MTX)

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Daytona Beach, Florida, United States, 32114
      • Pfizer Investigational Site
    • Fort Lauderdale, Florida, United States, 33301
      • Pfizer Investigational Site
    • Miramar, Florida, United States, 33025
      • Pfizer Investigational Site
  • Texas
    • Dallas, Texas, United States, 75247
      • Pfizer Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Pfizer

Publications and helpful links

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start: April 1, 2005
• Primary Completion (Actual): June 1, 2006
• Study Completion (Actual): June 1, 2006

Study Registration Dates

• First Submitted: December 4, 2012
• First Submitted That Met QC Criteria: December 6, 2012
• First Posted (Estimate): December 7, 2012

Study Record Updates

• Last Update Posted (Estimate): February 4, 2013
• Last Update Submitted That Met QC Criteria: January 29, 2013
• Last Verified: January 1, 2013

More Information

Terms related to this study

• Keywords: Pharmacokinetics; methotrexate (MTX); rheumatoid arthritis (RA); oral JAK inhibitor
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Protein Kinase Inhibitors; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Methotrexate; Tofacitinib
• Other Study ID Numbers: A3921013