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Mechanism Of Action
Tofacitinib is a Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Within the signaling pathway, JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) which modulate intracellular activity including gene expression. Tofacitinib modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs. JAK enzymes transmit cytokine signaling through pairing of JAKs (e.g., JAK1/JAK3, JAK1/JAK2, JAK1/TyK2, JAK2/JAK2). Tofacitinib inhibited the in vitro activities of JAK1/JAK2, JAK1/JAK3, and JAK2/JAK2 combinations with IC50 of 406, 56, and 1377 nM, respectively. However, the relevance of specific JAK combinations to therapeutic effectiveness is not known.
Treatment with XELJANZ was associated with dose-dependent reductions of circulating CD16/56+ natural killer cells, with estimated maximum reductions occurring at approximately 8-10 weeks after initiation of therapy. These changes generally resolved within 2-6 weeks after discontinuation of treatment. Treatment with XELJANZ was associated with dose-dependent increases in B cell counts. Changes in circulating T-lymphocyte counts and T-lymphocyte subsets (CD3+, CD4+ and CD8+) were small and inconsistent. The clinical significance of these changes is unknown.
After treatment with XELJANZ in patients with rheumatoid arthritis, rapid decreases in serum C-reactive protein (CRP) were observed and maintained throughout dosing. Changes in CRP observed with XELJANZ treatment do not reverse fully within 2 weeks after discontinuation, indicating a longer duration of pharmacodynamic activity compared to the pharmacokinetic half-life.
Following oral administration of XELJANZ, peak plasma concentrations are reached within 0.5-1 hour, elimination half-life is ~3 hours and a dose-proportional increase in systemic exposure was observed in the therapeutic dose range. Steady state concentrations are achieved in 24-48 hours with negligible accumulation after twice daily administration.
The absolute oral bioavailability of tofacitinib is 74%. Coadministration of XELJANZ with a high-fat meal resulted in no changes in AUC while Cmax was reduced by 32%. In clinical trials, XELJANZ was administered without regard to meals.
After intravenous administration, the volume of distribution is 87 L. The protein binding of tofacitinib is ~40%. Tofacitinib binds predominantly to albumin and does not appear to bind to ~1-acid glycoprotein. Tofacitinib distributes equally between red blood cells and plasma.
Metabolism and Elimination
Clearance mechanisms for tofacitinib are approximately 70% hepatic metabolism and 30% renal excretion of the parent drug. The metabolism of tofacitinib is primarily mediated by CYP3A4 with minor contribution from CYP2C19. In a human radiolabeled study, more than 65% of the total circulating radioactivity was accounted for by unchanged tofacitinib, with the remaining 35% attributed to 8 metabolites, each accounting for less than 8% of total radioactivity. The pharmacologic activity of tofacitinib is attributed to the parent molecule.
Pharmacokinetics in Rheumatoid Arthritis Patients
Population PK analysis in rheumatoid arthritis patients indicated no clinically relevant change in tofacitinib exposure, after accounting for differences in renal function (i.e., creatinine clearance) between patients, based on age, weight, gender and race (Figure 1). An approximately linear relationship between body weight and volume of distribution was observed, resulting in higher peak (Cmax) and lower trough (Cmin) concentrations in lighter patients. However, this difference is not considered to be clinically relevant. The between-subject variability (% coefficient of variation) in AUC of tofacitinib is estimated to be approximately 27%.
The effect of renal and hepatic impairment and other intrinsic factors on the pharmacokinetics of tofacitinib is shown in Figure 1.
Figure 1: Impact of Intrinsic Factors on Tofacitinib
* Supplemental doses are not necessary in patients after dialysis.
Reference values for weight, age, gender, and race comparisons are 70 kg, 55 years, male, and White, respectively; reference groups for renal and hepatic impairment data are subjects with normal renal and hepatic function.
Potential for XELJANZ to Influence the PK of Other Drugs
In vitro studies indicate that tofacitinib does not significantly inhibit or induce the activity of the major human drug-metabolizing CYPs (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) at concentrations exceeding 160 times the steady state Cmax of a 5 mg twice daily dose. These in vitro results were confirmed by a human drug interaction study showing no changes in the PK of midazolam, a highly sensitive CYP3A4 substrate, when coadministered with XELJANZ.
In rheumatoid arthritis patients, the oral clearance of tofacitinib does not vary with time, indicating that tofacitinib does not normalize CYP enzyme activity in rheumatoid arthritis patients. Therefore, coadministration with XELJANZ is not expected to result in clinically relevant increases in the metabolism of CYP substrates in rheumatoid arthritis patients.
In vitro data indicate that the potential for tofacitinib to inhibit transporters such as P-glycoprotein, organic anionic or cationic transporters at therapeutic concentrations is low.
Dosing recommendations for coadministered drugs following administration with XELJANZ are shown in Figure 2.
Figure 2: Impact of XELJANZ on PK of Other Drugs
Note: Reference group is administration of concomitant medication alone; OCT = Organic Cationic Transporter; MATE = Multidrug and Toxic Compound Extrusion
Potential for Other Drugs to Influence the PK of Tofacitinib
Since tofacitinib is metabolized by CYP3A4, interaction with drugs that inhibit or induce CYP3A4 is likely. Inhibitors of CYP2C19 alone or P-glycoprotein are unlikely to substantially alter the PK of tofacitinib. Dosing recommendations for XELJANZ for administration with CYP inhibitors or inducers are shown in Figure 3.
Figure 3: Impact of Other Drugs on PK of XELJANZ
Note: Reference group is administration of tofacitinib alone
The XELJANZ clinical development program included two dose-ranging trials and five confirmatory trials. Although other doses have been studied, the recommended dose of XELJANZ is 5 mg twice daily.
Dose selection for XELJANZ was based on two pivotal dose-ranging trials.
Dose-Ranging Study 1 was a 6-month monotherapy trial in 384 patients with active rheumatoid arthritis who had an inadequate response to a DMARD. Patients who previously received adalimumab therapy were excluded. Patients were randomized to 1 of 7 monotherapy treatments: XELJANZ 1, 3, 5, 10 or 15 mg twice daily, adalimumab 40 mg subcutaneously every other week for 10 weeks followed by XELJANZ 5 mg twice daily for 3 months, or placebo.
Dose-Ranging Study 2 was a 6-month trial in which 507 patients with active rheumatoid arthritis who had an inadequate response to MTX alone received one of 6 dose regimens of XELJANZ (20 mg once daily; 1, 3, 5, 10 or 15 mg twice daily), or placebo added to background MTX.
The results of XELJANZ-treated patients achieving ACR20 responses in Studies 1 and 2 are shown in Figure 4. Although a dose-response relationship was observed in Study 1, the proportion of patients with an ACR20 response did not clearly differ between the 10 mg and 15 mg doses. In Study 2, a smaller proportion of patients achieved an ACR20 response in the placebo and XELJANZ 1 mg groups compared to patients treated with the other XELJANZ doses. However, there was no difference in the proportion of responders among patients treated with XELJANZ 3, 5, 10, 15 mg twice daily or 20 mg once daily doses.
Figure 4: Proportion of Patients with ACR20 Response
at Month 3 in Dose-Ranging Studies 1 and 2
Study 1 was a dose-ranging monotherapy trial not designed to provide comparative effectiveness data and should not be interpreted as evidence of superiority to adalimumab.
Study I was a 6-month monotherapy trial in which 610 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to a DMARD (nonbiologic or biologic) received XELJANZ 5 or 10 mg twice daily or placebo. At the Month 3 visit, all patients randomized to placebo treatment were advanced in a blinded fashion to a second predetermined treatment of XELJANZ 5 or 10 mg twice daily. The primary endpoints at Month 3 were the proportion of patients who achieved an ACR20 response, changes in Health Assessment Questionnaire – Disability Index (HAQ-DI), and rates of Disease Activity Score DAS28-4(ESR) less than 2.6.
Study II was a 12-month trial in which 792 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to a nonbiologic DMARD received XELJANZ 5 or 10 mg twice daily or placebo added to background DMARD treatment (excluding potent immunosuppressive treatments such as azathioprine or cyclosporine). At the Month 3 visit, nonresponding patients were advanced in a blinded fashion to a second predetermined treatment of XELJANZ 5 or 10 mg twice daily. At the end of Month 6, all placebo patients were advanced to their second predetermined treatment in a blinded fashion. The primary endpoints were the proportion of patients who achieved an ACR20 response at Month 6, changes in HAQ-DI at Month 3, and rates of DAS28-4(ESR) less than 2.6 at Month 6.
Study III was a 12-month trial in 717 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to MTX. Patients received XELJANZ 5 or 10 mg twice daily, adalimumab 40 mg subcutaneously every other week, or placebo added to background MTX. Placebo patients were advanced as in Study II. The primary endpoints were the proportion of patients who achieved an ACR20 response at Month 6, HAQ-DI at Month 3, and DAS28-4(ESR) less than 2.6 at Month 6.
Study IV was a 2-year trial with a planned analysis at 1 year in which 797 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to MTX received XELJANZ 5 or 10 mg twice daily or placebo added to background MTX. Placebo patients were advanced as in Study II. The primary endpoints were the proportion of patients who achieved an ACR20 response at Month 6, mean change from baseline in van der Heijde-modified total Sharp Score (mTSS) at Month 6, HAQ-DI at Month 3, and DAS28-4(ESR) less than 2.6 at Month 6.
Study V was a 6-month trial in which 399 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to at least one approved TNF-inhibiting biologic agent received XELJANZ 5 or 10 mg twice daily or placebo added to background MTX. At the Month 3 visit, all patients randomized to placebo treatment were advanced in a blinded fashion to a second predetermined treatment of XELJANZ 5 or 10 mg twice daily. The primary endpoints at Month 3 were the proportion of patients who achieved an ACR20 response, HAQ-DI, and DAS28-4(ESR) less than 2.6.
Study VI was a 2-year monotherapy trial with a planned analysis at 1 year in which 952 MTX-na´ve patients with moderate to severe active rheumatoid arthritis received XELJANZ 5 or 10 mg twice daily or MTX dose-titrated over 8 weeks to 20 mg weekly. The primary endpoints were mean change from baseline in van der Heijde-modified Total Sharp Score (mTSS) at Month 6 and the proportion of patients who achieved an ACR70 response at Month 6.
The percentages of XELJANZ-treated patients achieving ACR20, ACR50, and ACR70 responses in Studies I, IV, and V are shown in Table 5. Similar results were observed with Studies II and III. In trials I-V, patients treated with either 5 or 10 mg twice daily XELJANZ had higher ACR20, ACR50, and ACR70 response rates versus placebo, with or without background DMARD treatment, at Month 3 and Month 6. Higher ACR20 response rates were observed within 2 weeks compared to placebo. In the 12-month trials, ACR response rates in XELJANZ-treated patients were consistent at 6 and 12 months.
Table 5: Proportion of Patients with an ACR Response
|Na||Percent of Patients|
|Monotherapy in Nonbiologic or Biologic DMARD Inadequate Respondersc||MTX Inadequate Respondersd||TNF Inhibitor Inadequate Responderse|
|Study I||Study IV||Study V|
|PBO||XELJANZ 5 mg Twice Daily||XELJANZ 10 mg Twice Dailyf||PBO+ MTX||XELJANZ 5 mg Twice Daily + MTX||XELJANZ 10 mg Twice Daily + MTXf||PBO + MTX||XELJANZ 5 mg Twice Daily + MTX||XELJANZ 10 mg Twice Daily + MTXf|
|a N is number of randomized and treated patients.
b NA Not applicable, as data for placebo treatment is not available beyond 3 months in Studies I and V due to placebo advancement.
c Inadequate response to at least one DMARD (biologic or nonbiologic) due to lack of efficacy or toxicity.
d Inadequate response to MTX defined as the presence of sufficient residual disease activity to meet the entry criteria.
e Inadequate response to a least one TNF inhibitor due to lack of efficacy and/or intolerance.
f The recommended dose of XELJANZ is 5 mg twice daily.
In Study IV, a greater proportion of patients treated with XELJANZ 5 mg or 10 mg twice daily plus MTX achieved a low level of disease activity as measured by a DAS28-4(ESR) less than 2.6 at 6 months compared to those treated with MTX alone (Table 6).
Table 6: Proportion of Patients with DAS28-4(ESR) Less
Than 2.6 with Number of Residual Active Joints
|Study IV||Placebo + MTX||XELJANZ 5 mg Twice Daily + MTX||XELJANZ 10 mg Twice Daily + MTX*|
|DAS28-4(ESR) Less Than 2.6|
|Proportion of responders at Month 6 (n)||1% (2)||6% (19)||13% (42)|
|Of responders, proportion with 0 active joints (n)||50% (1)||42% (8)||36% (15)|
|Of responders, proportion with 1 active joint (n)||0||5% (1)||17% (7)|
|Of responders, proportion with 2 active joints (n)||0||32% (6)||7% (3)|
|Of responders, proportion with 3 or more active joints (n)||50% (1)||21% (4)||40% (17)|
|*The recommended dose of XELJANZ is 5 mg twice daily.|
The results of the components of the ACR response criteria for Study IV are shown in Table 7. Similar results were observed for XELJANZ in Studies I, II, III, V, and VI.
Table 7: Components of ACR Response at Month 3
|Component (mean) a||Study IV|
|XELJANZ 5 mg Twice Daily + MTX
|XELJANZ 10 mgdTwice Daily + MTX
|Placebo + MTX
|Baseline||Month 3a||Baseline||Month 3a||Baseline||Month 3a|
|Number of tender joints (0-68)||24 (14)||13 (14)||23 (15)||10 (12)||23 (13)||18 (14)|
|Number of swollen joints (0-66)||14 (8)||6 (8)||14 (8)||6 (7)||14 (9)||10 (9)|
|Painb||58 (23)||34 (23)||58 (24)||29 (22)||55 (24)||47 (24)|
|Patient global assessmentb||58 (24)||35 (23)||57 (23)||29 (20)||54 (23)||47 (24)|
|Disability index (HAQ-DI)c||1.41 (0.68)||0.99 (0.65)||1.40 (0.66)||0.84 (0.64)||1.32 (0.67)||1.19 (0.68)|
|Physician global assessmentb||59 (16)||30 (19)||58 (17)||24 (17)||56 (18)||3 2) 4 (2|
|CRP (mg/L)||15.3 (19.0)||7.1 (19.1)||17.1 (26.9)||4.4 (8.6)||13.7 (14.9)||14.6 (18.7)|
|aData shown is mean (Standard Deviation) at Month 3.
bVisual analog scale: 0 = best, 100 = worst.
cHealth Assessment Questionnaire Disability Index: 0 = best, 3 = worst; 20 questions; categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities.
dThe recommended dose of XELJANZ is 5 mg twice daily.
The percent of ACR20 responders by visit for Study IV is shown in Figure 5. Similar responses were observed for XELJANZ in Studies I, II, III, V, and VI.
Figure 5: Percentage of ACR20 Responders by Visit for
Two studies were conducted to evaluate the effect of XELJANZ on structural joint damage. In Study IV and Study VI, progression of structural joint damage was assessed radiographically and expressed as change from baseline in mTSS and its components, the erosion score and joint space narrowing score, at Months 6 and 12. The proportion of patients with no radiographic progression (mTSS change less than or equal to 0) was also assessed.
In Study IV, XELJANZ 10 mg twice daily plus background MTX reduced the progression of structural damage compared to placebo plus MTX at Month 6. When given at a dose of 5 mg twice daily, XELJANZ exhibited similar effects on mean progression of structural damage (not statistically significant). These results are shown in Table 8. Analyses of erosion and joint space narrowing scores were consistent with the overall results.
In the placebo plus MTX group, 74% of patients experienced no radiographic progression at Month 6 compared to 84% and 79% of patients treated with XELJANZ plus MTX 5 or 10 mg twice daily.
In Study VI, XELJANZ monotherapy inhibited the progression of structural damage compared to MTX at Months 6 and 12 as shown in Table 8. Analyses of erosion and joint space narrowing scores were consistent with the overall results.
In the MTX group, 55% of patients experienced no radiographic progression at Month 6 compared to 73% and 77% of patients treated with XELJANZ 5 or 10 mg twice daily.
Table 8: Radiographic Changes at Months 6 and 12
N=139 Mean (SD)a
|XELJANZ 5 mg Twice Daily
N=277 Mean (SD)a
|XELJANZ 5 mg Twice Daily Mean Difference from Placebob (CI)||XELJANZ 10 mg Twice Dailyd N=290 Mean (SD) a||XELJANZ 10 mg Twice Daily Mean Difference from Placebob (CI)|
|Baseline||33 (42)||31 (48)||37 (54)|
|Month 6||0.5 (2.0)||0.1 (1.7)||-0.3 (-0.7, 0.0)||0.1 (2.0)||-0.4 (-0.8, 0.0)|
|MTX N=166 Mean (SD)a||XELJANZ 5 mg Twice Daily N=346 Mean (SD) a||XELJANZ 5 mg Twice Daily Mean Difference from MTXb (CI)||XELJANZ 10 mg Twice Dailyd N=369 Mean (SD) a||XELJANZ 10 mg Twice Daily Mean Difference from MTXb (CI)|
|Baseline||17 (29)||20 (40)||-||19 (39)||-|
|Month 6||0.8 (2.7)||0.2 (2.3)||-0.7 (-1.0, -0.3)||0.0 (1.2)||-0.8 (-1.2, -0.4)|
|Month 12||1.3 (3.7)||0.4 (3.0)||-0.9 (-1.4, -0.4)||0.0 (1.5)||-1.3 (-1.8, -0.8)|
|aSD = Standard Deviation
bDifference between least squares means XELJANZ minus placebo or MTX (95% CI = 95% confidence interval)
c Month 6 and Month 12 data are mean change from baseline.
d The recommended dose of XELJANZ is 5 mg twice daily.
Physical Function Response
Improvement in physical functioning was measured by the HAQ-DI. Patients receiving XELJANZ 5 and 10 mg twice daily demonstrated greater improvement from baseline in physical functioning compared to placebo at Month 3.
The mean (95% CI) difference from placebo in HAQ-DI improvement from baseline at Month 3 in Study III was -0.22 (-0.35, -0.10) in patients receiving 5 mg XELJANZ twice daily and -0.32 (-0.44, -0.19) in patients receiving 10 mg XELJANZ twice daily. Similar results were obtained in Studies I, II, IV and V. In the 12-month trials, HAQ-DI results in XELJANZ-treated patients were consistent at 6 and 12 months.
Other Health-Related Outcomes
General health status was assessed by the Short Form health survey (SF-36). In studies I, IV, and V, patients receiving XELJANZ 5 mg twice daily or XELJANZ 10 mg twice daily demonstrated greater improvement from baseline compared to placebo in physical component summary (PCS), mental component summary (MCS) scores and in all 8 domains of the SF-36 at Month 3.
Last reviewed on RxList: 7/15/2015
This monograph has been modified to include the generic and brand name in many instances.
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