Rheumatoid Arthritis
Conditions
Keywords
Pharmacokinetics, oral JAK inhibitor, methotrexate (MTX), rheumatoid arthritis (RA)
Brief summary
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.
Interventions
CP-690,550 30 mg q12h for 5 days
DRUGMethotrexate (MTX)
individual dose of methotrexate (stably dosed)
Sponsors
Pfizer
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve From Time Zero to 12 Hours [AUC (0-12)] 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 | AUC (0-12)= area under the plasma concentration time-curve from time zero (pre-dose) to 12 hours (0-12). |
| 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) | 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 | Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). |
| 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
| Measure | Time frame | Description |
|---|---|---|
| Plasma Decay Half-Life (t1/2) 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 is the time measured for the plasma concentration of MTX to decrease by one half. |
| Apparent Oral Clearance (CL/F) 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 | 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. |
| 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 | — |
| 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 | — |
| 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 | — |
| Renal Clearance (CL R) for CP-690,550 | 0 (pre-dose) through 24 hours post-dose on Day 6 and Day 7 | — |
| Plasma Decay Half-Life (t1/2) 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 is the time measured for the plasma concentration of CP-690,550 to decrease by one half. |
| Apparent Oral Clearance (CL/F) 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 | 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. |
| 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 | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Methotrexate + CP-690,550 Single oral dose of methotrexate (MTX) on Day 1 (15-25 milligram \[mg\], as per local prescribing practice); followed by CP-690,500 30 mg tablet orally every twelve hours from Day 3 to Day 6; followed by single oral dose of MTX (15-25 mg, as per local prescribing practice) and single oral dose of CP-690,500 30 mg tablet orally, on Day 7. | 12 |
| Total | 12 |
Baseline characteristics
| Characteristic | Methotrexate + CP-690,550 |
|---|---|
| Age Continuous | 57.3 years STANDARD_DEVIATION 10.2 |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 5 / 12 | 6 / 12 | 5 / 12 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 | 0 / 12 |
Outcome results
Primary
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).
Time frame: 0 (pre-dose), 0.25, 0.5, 1, 2, 3, 4, 8 and 12 hours post-dose on Day 6 and Day 7
Population: The pharmacokinetic (PK) analysis population included all enrolled participants with PK parameters of interest for at least 1 period of fixed sequence.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CP-690,500 | Area Under the Curve From Time Zero to 12 Hours [AUC (0-12)] for CP-690,550 | 1370 nanogram*hour/milliliter (ng*hr/mL) | Standard Deviation 423 |
| Methotrexate + CP-690,500 | Area Under the Curve From Time Zero to 12 Hours [AUC (0-12)] for CP-690,550 | 1410 nanogram*hour/milliliter (ng*hr/mL) | Standard Deviation 425 |
Comparison: Natural log transformed, AUC (0-12) of CP-690,550 was analyzed using mixed effect model with treatment as fixed effects and participant as a random effect. The adjusted mean differences and 90% confidence intervals (CIs) for the differences were exponentiated to provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90% CIs for the ratios.90% CI: [99, 107.29]
Primary
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).
Time frame: 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
Population: PK analysis population included all enrolled participants with PK parameters of interest for at least 1 period of fixed sequence.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CP-690,500 | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) for Methotrexate (MTX) | 1850 ng*hr/mL | Standard Deviation 685 |
| Methotrexate + CP-690,500 | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) for Methotrexate (MTX) | 1720 ng*hr/mL | Standard Deviation 753 |
Comparison: Natural log transformed, AUClast of MTX was analyzed using mixed effect model with treatment as fixed effects and participant as a random effect. The adjusted mean differences and 90% CIs for the differences were exponentiated to provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90% CIs for the ratios.90% CI: [77.38, 103.57]
Primary
Maximum Observed Plasma Concentration (Cmax) for CP-690,550
Time frame: 0 (pre-dose), 0.25, 0.5, 1, 2, 3, 4, 8 and 12 hours post-dose on Day 6 and Day 7
Population: The PK analysis population included all enrolled participants with PK parameters of interest for at least 1 period of fixed sequence.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CP-690,500 | Maximum Observed Plasma Concentration (Cmax) for CP-690,550 | 375 ng/mL | Standard Deviation 91.6 |
| Methotrexate + CP-690,500 | Maximum Observed Plasma Concentration (Cmax) for CP-690,550 | 384 ng/mL | Standard Deviation 84.8 |
Comparison: Natural log transformed, Cmax of CP-690,550 was analyzed using mixed effect model with treatment as fixed effects and participant as a random effect. The adjusted mean differences and 90% CIs for the differences were exponentiated to provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90% CIs for the ratios.90% CI: [93.79, 112.47]
Primary
Maximum Observed Plasma Concentration (Cmax) for Methotrexate (MTX)
Time frame: 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
Population: PK analysis population included all enrolled participants with PK parameters of interest for at least 1 period of fixed sequence.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CP-690,500 | Maximum Observed Plasma Concentration (Cmax) for Methotrexate (MTX) | 478 ng/mL | Standard Deviation 106 |
| Methotrexate + CP-690,500 | Maximum Observed Plasma Concentration (Cmax) for Methotrexate (MTX) | 433 ng/mL | Standard Deviation 175 |
Comparison: Natural log transformed, Cmax of MTX was analyzed using mixed effect model with treatment as fixed effects and participant as a random effect. The adjusted mean differences and 90% CIs for the differences were exponentiated to provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90% CIs for the ratios.90% CI: [76.03, 100.12]
Secondary
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.
Time frame: 0 (pre-dose), 0.25, 0.5, 1, 2, 3, 4, 8 and 12 hours post-dose on Day 6 and Day 7
Population: PK analysis population included all enrolled participants with PK parameters of interest for at least 1 period of fixed sequence.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CP-690,500 | Apparent Oral Clearance (CL/F) for CP-690,550 | 23200 mL/hr | Standard Deviation 8380 |
| Methotrexate + CP-690,500 | Apparent Oral Clearance (CL/F) for CP-690,550 | 23511 mL/hr | Standard Deviation 8784 |
Secondary
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.
Time frame: 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
Population: PK analysis population included all enrolled participants with PK parameters of interest for at least 1 period of fixed sequence.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CP-690,500 | Apparent Oral Clearance (CL/F) for Methotrexate (MTX) | 9890 mL/hr | Standard Deviation 3370 |
| Methotrexate + CP-690,500 | Apparent Oral Clearance (CL/F) for Methotrexate (MTX) | 11500 mL/hr | Standard Deviation 5430 |
Secondary
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.
Time frame: 0 (pre-dose), 0.25, 0.5, 1, 2, 3, 4, 8 and 12 hours post-dose on Day 6 and Day 7
Population: PK analysis population included all enrolled participants with PK parameters of interest for at least 1 period of fixed sequence.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CP-690,500 | Plasma Decay Half-Life (t1/2) for CP-690,550 | 2.64 hour | Standard Deviation 0.356 |
| Methotrexate + CP-690,500 | Plasma Decay Half-Life (t1/2) for CP-690,550 | 3.12 hour | Standard Deviation 0.74 |
Secondary
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.
Time frame: 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
Population: PK analysis population included all enrolled participants with PK parameters of interest for at least 1 period of fixed sequence.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CP-690,500 | Plasma Decay Half-Life (t1/2) for Methotrexate (MTX) | 2.87 hour | Standard Deviation 0.962 |
| Methotrexate + CP-690,500 | Plasma Decay Half-Life (t1/2) for Methotrexate (MTX) | 3.36 hour | Standard Deviation 1.13 |
Secondary
Renal Clearance (CL R) for CP-690,550
Time frame: 0 (pre-dose) through 24 hours post-dose on Day 6 and Day 7
Population: PK analysis population included all enrolled participants with PK parameters of interest for at least 1 period of fixed sequence.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CP-690,500 | Renal Clearance (CL R) for CP-690,550 | 5490 litre/hour (L/hr) | Standard Deviation 2890 |
| Methotrexate + CP-690,500 | Renal Clearance (CL R) for CP-690,550 | 5240 litre/hour (L/hr) | Standard Deviation 2630 |
Secondary
Renal Clearance (CL R) for Methotrexate (MTX)
Time frame: 0 (pre-dose) through 24 hours post-dose on Day 1 and Day 7
Population: PK analysis population included all enrolled participants with PK parameters of interest for at least 1 period of fixed sequence.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CP-690,500 | Renal Clearance (CL R) for Methotrexate (MTX) | 10.2 L/hr | Standard Deviation 4.56 |
| Methotrexate + CP-690,500 | Renal Clearance (CL R) for Methotrexate (MTX) | 8.95 L/hr | Standard Deviation 4.64 |
Secondary
Time to Reach Maximum Observed Plasma Concentration (Tmax) for CP-690,550
Time frame: 0 (pre-dose), 0.25, 0.5, 1, 2, 3, 4, 8 and 12 hours post-dose on Day 6 and Day 7
Population: PK analysis population included all enrolled participants with PK parameters of interest for at least 1 period of fixed sequence.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CP-690,500 | Time to Reach Maximum Observed Plasma Concentration (Tmax) for CP-690,550 | 1.00 hour |
| Methotrexate + CP-690,500 | Time to Reach Maximum Observed Plasma Concentration (Tmax) for CP-690,550 | 1.00 hour |
Secondary
Time to Reach Maximum Observed Plasma Concentration (Tmax) for Methotrexate (MTX)
Time frame: 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
Population: PK analysis population included all enrolled participants with PK parameters of interest for at least 1 period of fixed sequence.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CP-690,500 | Time to Reach Maximum Observed Plasma Concentration (Tmax) for Methotrexate (MTX) | 1.00 hour |
| Methotrexate + CP-690,500 | Time to Reach Maximum Observed Plasma Concentration (Tmax) for Methotrexate (MTX) | 1.25 hour |
Secondary
Total Amount of Unchanged Drug Excreted in the Urine From Time Zero to 12 Hours (Ae[0-12]) for CP-690,550
Time frame: 0 (pre-dose) through 12 hours post-dose on Day 6 and Day 7
Population: PK analysis population included all enrolled participants with PK parameters of interest for at least 1 period of fixed sequence.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CP-690,500 | Total Amount of Unchanged Drug Excreted in the Urine From Time Zero to 12 Hours (Ae[0-12]) for CP-690,550 | 6.65 milligram | Standard Deviation 2.26 |
| Methotrexate + CP-690,500 | Total Amount of Unchanged Drug Excreted in the Urine From Time Zero to 12 Hours (Ae[0-12]) for CP-690,550 | 6.58 milligram | Standard Deviation 2.34 |
Secondary
Total Amount of Unchanged Drug Excreted in the Urine From Time Zero to 24 Hours (Ae[0-24]) for Methotrexate (MTX)
Time frame: 0 (pre-dose) through 24 hours post-dose on Day 1 and Day 7
Population: PK analysis population included all enrolled participants with PK parameters of interest for at least 1 period of fixed sequence.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CP-690,500 | Total Amount of Unchanged Drug Excreted in the Urine From Time Zero to 24 Hours (Ae[0-24]) for Methotrexate (MTX) | 18.1 milligram | Standard Deviation 9.31 |
| Methotrexate + CP-690,500 | Total Amount of Unchanged Drug Excreted in the Urine From Time Zero to 24 Hours (Ae[0-24]) for Methotrexate (MTX) | 13.2 milligram | Standard Deviation 4.38 |