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Br J Clin Pharmacol. Feb 2010; 69(2): 143–151.
PMCID: PMC2824475

Co-administration of the JAK inhibitor CP-690,550 and methotrexate is well tolerated in patients with rheumatoid arthritis without need for dose adjustment



To investigate the effects of methotrexate (MTX) on the pharmacokinetics (PK) of CP-690,550, a novel Janus kinase (JAK) inhibitor in development as a therapy for rheumatoid arthritis (RA), to determine the effects of multiple doses 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.


This was a fixed-dose drug–drug interaction study. Twelve patients diagnosed with RA for at least 6 months were enrolled in a Phase I, open-label study of the PK of multiple doses of CP-690,550 (30 mg b.i.d.) and single doses of MTX (15–25 mg per week).


All patients completed the study and were evaluated for PK and safety. CP-690,550 exposure was not affected by co-administration with MTX; AUC12 ratio (CP-690,550 + MTX/CP-690,550) was 103.06% [90% confidence interval (CI) 99.00, 107.29]. MTX exposure decreased by 10%; AUC12 ratio (CP-690,550 + MTX/MTX) was 89.53% (90% CI 77.38, 103.57), which was not considered clinically significant. Co-administration of CP-690,550 and MTX was safe and well tolerated. There were no serious adverse events or withdrawals from the study and there was no trend in the incidence or severity of adverse events across treatments.


Co-administration of CP-690,550 and MTX was safe and well tolerated. There was no clinically significant effect on the PK profile of either drug. Therefore, dose adjustments should not be required when co-administering CP-690,550 and MTX.

Keywords: CP-690,550; methotrexate; rheumatoid arthritis


  • CP-690,550 is a novel JAK inhibitor in development as a therapy for rheumatoid arthritis.
  • Methotrexate is the cornerstone of combination treatment for rheumatoid arthritis.
  • The safety and tolerability of co-administration of CP-690,550 with methotrexate have not been addressed to date.


  • This study in patients with rheumatoid arthritis shows that there are no clinically relevant effects on the pharmacokinetics of either drug following short-term co-administration.
  • Co-administration of CP-690,550 and methotrexate was safe and well tolerated.


Rheumatoid arthritis (RA) is a chronic, progressive, autoimmune disease leading to joint damage and bone destruction, deformity, disability, and even premature death [1]. The majority of studies carried out in Northern Europe and North America report estimates of disease prevalence ranging from 0.5 to 1%; a recent study estimated the prevalence of RA among US adults to be 0.6% [2].

There is currently no cure for RA, therefore the aim of treatment is to prevent or control joint damage, prevent loss of function, and decrease symptoms. Disease-modifying antirheumatic drugs (DMARDs) have the potential to reduce joint damage, preserve joint integrity and function, and improve the quality of life of the patient with RA [1, 3]. Methotrexate (MTX) remains the current gold standard DMARD and is considered by the majority of physicians as the initial drug of choice in early RA [4]. Single DMARD therapy frequently fails to control RA symptoms adequately or delay disease progression. Consequently, in recent years combinations of nonbiological DMARDs or nonbiological DMARD with a biological DMARD have been increasingly prescribed. The majority of trials carried out over the last decade have included MTX as part of the combination [5]. Thus, MTX remains the cornerstone of combination therapy in patients with RA [1, 4, 6, 7]. The possibility of drug–drug interactions or additive adverse event (AE) profiles must be considered before combining new drugs with MTX.

Janus kinase 3 (JAK3) is a key component in the signalling pathways of the type I cytokines interleukin-2, -4, -7, -9, -15 and -21, through its interaction with the common gamma chain (γc) subunit of the respective cytokine receptors [8]. Type I cytokines are critically involved in lymphocyte activation, proliferation and function [9]. JAK3 is primarily expressed in activated T lymphocytes and B lymphocytes and is constitutively expressed in natural killer cells [1012]. Increasingly, evidence suggests that activated T cells and B cells play a significant role in the pathogenesis of RA [13, 14].

CP-690,550 is an orally active JAK inhibitor currently in development as a DMARD for the treatment of RA and as an immunosuppressive agent to prevent allograft rejection and to treat various autoimmune diseases. CP-690,550 is a potent inhibitor of JAK1/3- and JAK1-dependent STAT activities with IC50 values in the range 26–63 nM, whereas IC50 values for JAK2-mediated pathways ranged from 129 to 501 nM [15]. The pharmacokinetic profile of CP-690,550 in RA patients is linear, and is characterized by rapid absorption and rapid elimination with a half-life of approximately 3 h [16]. CP-690,550 has demonstrated efficacy in a Phase IIa trial in patients with active RA [17]. All three dose levels of CP-690,550 (5, 15 or 30 mg, b.i.d.) were highly efficacious, compared with placebo, in the treatment of signs and symptoms of RA [17], and in improving the pain, function and health status of patients with RA, beginning at week 1 and sustained to week 6 [18]. CP-690,550 has a novel mode of action that may offer advantages over older, less selective immunosuppressants. In addition, the oral formulation of CP-690,550 may provide a more convenient treatment regimen than therapies that require parenteral administration.

Treatment options for CP-690,550 in the treatment of RA may include co-administration with MTX; here we report the results of a Phase I, open-label study of the pharmacokinetics (PK) of multiple doses of CP-690,550 and single doses of oral MTX in RA patients. This study was performed in preparation for conducting a Phase IIb study in RA patients on a background of stable MTX dosing.


This study was carried out in the USA. The study was sponsored by Pfizer Inc. and was carried out in compliance with the ethical principles originating in, or derived from, the Declaration of Helsinki, and in compliance with all International Conference of Harmonization Good Clinical Practice Guidelines. In addition, all local regulatory requirements were followed. The final protocol and informed consent documentation were reviewed and approved by the Institutional Review Boards at the investigational centres participating in the study.

The objectives of this study were to estimate the effects of MTX on the PK of CP-690,550, estimate the effects of multiple doses of CP-690,550 on the PK of MTX, and evaluate the short-term safety and tolerability of co-administration of CP-690,550 and MTX.


Patients were 18–70 years of age and had a diagnosis of RA based on the American College of Rheumatology Revised Criteria for at least 6 months prior to enrolment. Patients must have been receiving an oral stable dose of MTX (15–25 mg week−1, administered as a single dose), made by the same manufacturer, for a minimum of 4 weeks prior to enrolment. Key exclusion criteria included evidence of haematopoietic disorders (haemoglobin <10 g dl−1; haematocrit <32%; white blood cell count <3.0 × 109 l−1; platelet count <100 × 109 l−1 at screening) and an estimated glomerular filtration rate (Cockcroft − Gault) ≤60 ml min−1.

Patients were to continue taking stable background RA therapy (defined as not starting a new drug or changing dosage within 7 days or five half-lives prior to enrolment), including nonsteroidal anti-inflammatory drugs, cyclooxygenase 2 inhibitors and low-dose oral corticosteroids (≤10 mg prednisone or equivalent per day). Other prescription or nonprescription drugs, vitamins and dietary supplements were to be stopped within 14 days prior to the first dose of trial medication and throughout the course of the trial.

Study treatment

The pharmacodynamic effects of MTX are long-lived, therefore it was neither ethical nor feasible to require patients to wash-out MTX until their RA flared. Consequently, the study was designed to allow wash-out of MTX based on typical MTX PK before evaluating the PK of CP-690,550. Patients were confined to the clinical research unit from day 0 until discharge on day 9 and were required to return for a follow-up visit prior to their next weekly MTX dose (approximately days 11–13).

The overall study design is shown in Table 1. Eligible patients received their individualized dose of MTX on day 1 and blood samples were collected for 48 h, until day 3, for the analysis of MTX. Patients received 30 mg CP-690,550 every 12 h from day 3 (after the last blood sample for MTX analysis) until day 6. On day 6, serial blood samples were taken for analysis of CP-690,550. On day 7, patients received their weekly MTX dose combined with a 30-mg dose of CP-690,550; blood samples were collected for the following 48 h for analysis of CP-690,550 and MTX.

Table 1
Overall study design

Pharmacokinetic evaluations

Blood samples for PK analysis of CP-690,550 were collected on day 1 at 0 h (predose), days 6 and 7 at 0 (predose), 0.25, 0.5, 1, 2, 3, 4, 8 and 12 h, and also at 24 and 48 h post day 7 dosing. Blood samples for PK analysis of MTX were collected on days 1–3 and days 7–9 at 0 (predose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24 and 48 h. Samples were analysed for CP-690,550 concentrations using validated solid-phase extraction followed by liquid chromatography/tandem mass spectrometry (LC/MS/MS) methodology. Samples were analysed for MTX concentration using a validated, sensitive, and specific LC/MS/MS method. Table 2 summarizes assay conditions and performance. Urine samples were collected at day 1 (prior to dosing). Following MTX dosing on days 1 and 7, and CP-690,550 dosing on days 6 and 7, urine was collected in two batches of 0–12 and 12–24 h after dose. Urine samples were assayed for CP-690,550 concentrations using a validated solid-phase extraction followed by an LC/MS/MS method. Samples were analysed for MTX concentrations using a validated, sensitive and specific high-performance liquid chromatograph with ultraviolet detection method.

Table 2
Summary of bioanalytical methods

Individual plasma concentration–time data for CP-690,550 were analysed by noncompartmental methods using the WinNonlin Enterprise PK software package (Version 3.2). All concentrations that were below the lower limit of quantification (CP-690,550 concentrations <1.00 ng ml−1; MTX concentrations <5.0 ng ml−1) were assigned a value of zero. Additionally, mean concentrations were reported as 0 ng ml−1 if >50% of the concentration data at a particular time point was below the lower limit of quantification.

Safety evaluations

All observed or volunteered AEs were recorded and graded according to relationship to study treatment and severity (mild, moderate, severe). Safety laboratory tests (haematology, urinalysis and chemistry) were carried out at screening, on days 1, 3 and 9, and at follow-up. Blood pressure and pulse rate were measured at screening, days 1–9, and at follow-up. Electrocardiograms were performed at screening, 2 h post dose on days 1, 3 and 7, on day 9, and at follow-up.

Statistical analysis

The planned sample size of at least 12 patients allowed for calculation of the probable 90% confidence intervals (CI) that could be expected for various possible relative exposure estimates of AUC and Cmax for CP-690,550 in the presence and absence of MTX, and for MTX in the presence and absence of CP-690,550. These calculations were based on estimates of within-subject standard deviations of 0.31 and 0.28 for loge AUC and logeCmax, respectively, for CP-690,550, as obtained from a previous study of CP-690,550 [19]. It was also assumed that estimates of within-subject standard deviations of loge AUC and logeCmax of MTX would be no greater than 0.28. If the estimated relative bioavailability for CP-690,550 or MTX was 100%, then the probability that the 90% CIs for AUC and Cmax would be within 80% and 125%, respectively, was at least 0.8.

To estimate the effects on PK parameters, a mixed-effect model was used to analyse log-transformed data. The model included treatment as a fixed effect and subject as a random effect. The model was implemented using SAS Proc Mixed, with REML estimation method, variance-covariance structure of compound symmetry and Satterthwaite degrees of freedom algorithm.

Adjusted geometric means were calculated for AUC12 or 24, Cmax, CL/F, Ae12 or 24 and CLR; descriptive statistics were calculated for t1/2 (arithmetic mean) and Tmax (median).


Patient disposition and study treatment

A total of 12 patients were enrolled and received study treatment (Figure 1). The demographics of the study population are summarized in Table 3.

Table 3
Demographic characteristics
Figure 1
CONSORT diagram

All patients completed the study and were included in the analysis. One subject missed one dose of CP-690,550 due to mild lower leg pain, which resolved the following day.

Pharmacokinetic results

The CP-690,550 PK analysis is summarized in Table 4. The mean steady-state exposure parameters following multiple oral doses of CP-690,550 (30 mg every 12 h) co-administered with single-dose MTX were similar to exposures following multiple dosing of CP-690,550 alone. The exposure parameters observed following multiple dosing of CP-690,550 alone are consistent with those seen previously in patients with RA [16]. Neither total amounts of CP-690,550 excreted in urine (Ae12) nor renal clearance (CLR) were affected by a single dose of MTX. In both treatment periods, CP-690,550 peak plasma concentration was reached within 0.5–1 h following administration (Figure 2). All 90% CIs for log-transformed PK parameters were wholly within the 80–125% no-effect limit.

Table 4
Statistical analysis of PK parameters of CP-690,550
Figure 2
Effect of methotrexate on CP-690,550 plasma concentration (mean ± standard deviation). 30 mg CP-690,550 alone (An external file that holds a picture, illustration, etc.
Object name is bcp0069-0143-fu1.jpg); 30 mg CP-690,550 + MTX (An external file that holds a picture, illustration, etc.
Object name is bcp0069-0143-fu2.jpg)

The MTX PK analysis is summarized in Table 5. Following multiple dosing of CP-690,550 co-administered with single-dose MTX, the MTX exposures, AUC24 and Cmax, decreased by 10% and 13%, respectively, when compared with exposure following administration of MTX alone (Figure 3). The Ae24 and CLR of MTX were decreased by 23% and 14%, respectively, while CL/F increased by 11% and t1/2 was delayed by 0.5 h. Tmax appeared to be unaffected.

Table 5
Statistical analysis of PK parameters of MTX
Figure 3
Effect of CP-690,550 on methotrexate plasma concentration (mean ± standard deviation). MTX alone (An external file that holds a picture, illustration, etc.
Object name is bcp0069-0143-fu3.jpg); MTX + 30 mg CP-690,550 (An external file that holds a picture, illustration, etc.
Object name is bcp0069-0143-fu4.jpg)

None of the observed PK interactions was considered clinically significant.

Safety results

A total of 34 AEs were reported during the study (Table 6). There were no obvious trends in the incidence, type or severity of AEs across treatments. Five patients reported seven AEs after treatment with MTX alone, six patients reported 15 AEs after treatment with CP-690,550 alone, and five patients reported 12 AEs after combination treatment (Table 7). Thirty-one of the 34 AEs were mild in intensity and the remaining three were moderate. The three moderate events (one migraine headache and two tension headaches) all occurred in one patient who had a history of migraine. There were two haematological AEs, of anaemia, both in the CP-690,550 plus MTX treatment group and mild in severity. One patient had haemoglobin levels of 11.8 mg on day 0 and 11.7 mg after dosing on day 11, and haematocrit levels of 36.9% on day 0 and 29.8% on day 11; the second patient had haemoglobin levels of 13.1 mg on day 0 and 10.7 mg at follow-up, and haematocrit levels of 40.7% on day 0 and 33.2% at follow-up. Four events (disorientation, dizziness, headache, and hot flush) reported by two patients in the CP-690,550 treatment group were considered treatment related by the study investigator. These were all mild in intensity and resolved rapidly. There were no serious AEs or permanent discontinuations during the study. Two patients were temporarily discontinued from administration of CP-690,550 due to AEs not related to the study drug. Both temporary discontinuations missed one dose; one patient experienced mild leg pain and the other patient experienced a mild vasovagal episode during a blood draw. These events resolved prior to the next dose so that the patients were able to continue dosing as scheduled.

Table 7
Incidence of treatment-emergent adverse events; all causalities (treatment-related)
Table 6
Incidence of treatment-emergent adverse events; all causalities (treatment-related)

There were no clinically significant laboratory test results and no clinically significant mean changes from baseline for any vital-sign parameter or ECG parameter.


The use of MTX as monotherapy for the treatment of RA may not fully control disease activity. Consequently, the use of MTX in combination with other nonbiological DMARDs has been increasingly investigated. Combination therapy of biological and nonbiological DMARDs with MTX has proven to be more effective than monotherapy [2022]. Even with this approach, 40–60% of patients fail to achieve significant improvements in disease activity; therefore, the possibility that combinations of MTX with new agents, such as CP-690,550, will offer superior efficacy and tolerability profiles remains, and should be investigated.

The results of this study show that co-administration of CP-690,550 with MTX had no statistically or clinically significant effect on the PK profile of CP-690,550. The small changes in MTX PK suggest that no modifications to the individualized dosing of MTX are warranted. One possible mechanism behind these small changes in MTX PK involves transporters. It has been demonstrated in rats that breast cancer resistance protein and multidrug resistance-associated proteins are involved in the regional difference in absorption of MTX along the intestine, which depends on their expression sites [22]. MTX excretion has also been shown to be dependent on organic anionic transporter [23]. Inhibition of one or more of these transporters in the intestine or kidney may result in changes in MTX PK, including effects in one location (e.g. intestine) countered by effects in another (e.g. kidney), thus resulting in increased CL/F and t1/2 but reduced CLR in the presence of an interacting agent. The clearance mechanisms of CP-690,550 appear to be 70% nonrenal (metabolism via CYP3A4 and CYP2C19) and 30% renal (filtration and secretion) (data on file, Pfizer Inc.). The potential for CP-690,550 to interact with these transporters is unknown; however, given the magnitude of the observed changes, these effects do not carry any clinical relevance for MTX PK. Based on the PK results in this study, no dose adjustment is required when co-administering CP-690,550 and MTX.

MTX therapy can result in haematological AEs [23] and, in a previous study of CP-690,550 in patients with RA, haematological AEs occurred more frequently in the CP-690,550 treatment groups than in the placebo group [17]. While the haematological AEs in the CP-690,550 groups were mostly mild to moderate in severity, and were reversible on cessation of treatment, this observation raises the possibility that co-administration of CP-690,550 with MTX could lead to more frequent or severe haematological AEs. In the current study only two haematological AEs, of anaemia, occurred. Overall, co-administration of CP-690,550 with MTX appeared to be safe and well tolerated with no serious or severe AEs reported. Furthermore, in a larger subsequent study, CP-690,550 and MTX co-administration was efficacious compared with placebo for up to 12 weeks and only minor changes in haemoglobin were recorded [24].

Following previous Phase II studies of CP-690,550 in patients with RA, which evaluated doses of CP-690,550 up to 30 mg b.i.d. [17, 24], a maximum dose of 10 mg b.i.d. is being investigated in Phase III studies. The dose of CP-690,550 used in this present study is three times higher than the highest dose planned for Phase III studies of the combination, which should cover the extremes of exposures observed with the therapeutic dose.

The fixed-sequence design is the simplest design to estimate the effect of both drugs on one another as suggested by regulatory guidance. The limitation of the approach is that period effects will be confounded with treatment effects. However, neither CP-690,550 nor MTX showed time dependency in PK, and the wash-out of MTX was adequate (all predose concentrations of MTX were below the limit of quantification) to evaluate the effects on CP-690,550.

Larger, long-term studies of concomitant administration of CP-690,550 and MTX are required to confirm the efficacy and safety of this combination in larger patient populations and evaluate the need for dose adjustments based on efficacy and/or safety data. To this end, the combination of CP-690,550 and MTX is currently undergoing further evaluation in patients with RA.

Competing interests

S.C. has received funds for research and fees for consulting from Pfizer Inc. and has shares in Pfizer Inc. S.Z. and B.W. are employees of Pfizer Inc. and own stock in the company.

This research was sponsored by Pfizer Inc. The authors thank Sriram Krishnaswami and Barbara Duncan for their assistance with data analysis. Editorial support was provided by Dr Clemence Hindley at Complete Medical Communications and was funded by Pfizer Inc.


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