Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic groups: Immunosuppressants, Janus-associated kinase (JAK) inhibitors; ATC code: L04AF01

Mechanism of action

Tofacitinib is a potent, selective inhibitor of the JAK family. In enzymatic assays, tofacitinib inhibits JAK1, JAK2, JAK3, and to a lesser extent TyK2. In contrast, tofacitinib has a high degree of selectivity against other kinases in the human genome. In human cells, tofacitinib preferentially inhibits signalling by heterodimeric cytokine receptors that associate with JAK3 and/or JAK1 with functional selectivity over cytokine receptors that signal via pairs of JAK2. Inhibition of JAK1 and JAK3 by tofacitinib attenuates signalling of interleukins (IL-2, -4, -6, -7, -9, -15, -21) and type I and type II interferons, which will result in modulation of the immune and inflammatory response.



Pharmacodynamic effects

In patients with RA, treatment up to 6 months with tofacitinib was associated with dose-dependent reductions of circulating CD16/56+ natural killer (NK) 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 tofacitinib 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.

Following long-term treatment (median duration of tofacitinib treatment of approximately 5 years), CD4+ and CD8+ counts showed median reductions of 28% and 27%, respectively, from baseline. In contrast to the observed decrease after short-term dosing, CD16/56+ natural killer cell counts showed a median increase of 73% from baseline. CD19+ B cell counts showed no further increases after long-term tofacitinib treatment. All these lymphocyte subset changes returned toward baseline after temporary discontinuation of treatment. There was no evidence of a relationship between serious or opportunistic infections or herpes zoster and lymphocyte subset counts (see section 4.2 for absolute lymphocyte count monitoring).

Changes in total serum IgG, IgM, and IgA levels over 6-month tofacitinib dosing in patients with RA were small, not dose-dependent and similar to those seen on placebo, indicating a lack of systemic humoral suppression.

After treatment with tofacitinib in RA patients, rapid decreases in serum C-reactive protein (CRP) were observed and maintained throughout dosing. Changes in CRP observed with tofacitinib treatment do not reverse fully within 2 weeks after discontinuation, indicating a longer duration of pharmacodynamic activity compared to the half-life.

Vaccine studies

In a controlled clinical study of patients with RA initiating tofacitinib 10 mg twice daily or placebo, the number of responders to influenza vaccine was similar in both groups: tofacitinib (57%) and placebo (62%). For pneumococcal polysaccharide vaccine the number of responders was as follows: 32% in patients receiving both tofacitinib and MTX; 62% for tofacitinib monotherapy; 62% for MTX monotherapy; and 77% for placebo. The clinical significance of this is unknown, however, similar results were obtained in a separate vaccine study with influenza and pneumococcal polysaccharide vaccines in patients receiving long-term tofacitinib 10 mg twice daily.

A controlled study was conducted in patients with RA on background MTX immunised with a live attenuated herpes virus vaccine 2 to 3 weeks before initiating a 12-week treatment with tofacitinib 5 mg twice daily or placebo. Evidence of humoral and cell-mediated responses to VZV was observed in both tofacitinib and placebo-treated patients at 6 weeks. These responses were similar to those observed in healthy volunteers aged 50 years and older. A patient with no previous history of varicella infection and no anti-varicella antibodies at baseline experienced dissemination of the vaccine strain of varicella 16 days after vaccination. Tofacitinib was discontinued and the patient recovered after treatment with standard doses of antiviral medicinal product. This patient subsequently made a robust, though delayed, humoral and cellular response to the vaccine (see section 4.4).

Clinical efficacy and safety

Clinical response
The tofacitinib Phase 3 program for JIA consisted of one completed Phase 3 trial (Study JIA-I [A3921104]) and one ongoing long-term extension (LTE) (A3921145) trial. In these studies the following JIA subgroups were included: patients with either RF+ or RF- polyarthritis, extended oligoarthritis, systemic JIA with active arthritis and no current systemic symptoms (referred as pJIA dataset) and two separate subgroups of patients with juvenile PsA and enthesitis-related arthritis 
(ERA). However, the pJIA efficacy population only includes the subgroups with either RF+ or RF- polyarthritis or extended oligoarthritis; inconclusive results have been seen in the subgroup of patients with systemic JIA with active arthritis and no current systemic symptoms. Patients with juvenile PsA are included as separate efficacy subgroup. ERA patients are not included in the efficacy analysis.

All eligible patients in Study JIA-I received open-label tofacitinib 5 mg film-coated tablets twice daily or tofacitinib oral solution weight-based equivalent twice daily for 18 weeks (run-in phase); patients who achieved at least a JIA ACR30 response at the end of the open-label phase were randomised (1:1) to either active tofacitinib 5 mg film-coated tablets or tofacitinib oral solution, or placebo in the 26-week double-blind, placebo-controlled phase. Patients who did not achieve a JIA ACR30 response at the end of the open-label run-in phase or experienced a single episode of disease flare at any time were discontinued from the study. A total of 225 patients were enrolled in the open-label run-in phase.
Of these, 173 (76.9%) patients were eligible to be randomised into the double-blind phase to either active tofacitinib 5 mg film-coated tablets or tofacitinib oral solution weight-based equivalent twice daily (n=88) or placebo (n=85). There were 58 (65.9%) patients in the tofacitinib group and 58 (68.2%) patients in the placebo group taking MTX during the double-blind phase, which was permitted but not required per the protocol.

There were 133 patients with pJIA [RF+ or RF- polyarthritis and extended oligoarthritis] and 15 with juvenile PsA randomised into the double-blind phase of the study and included in the efficacy analyses presented below.

Signs and symptoms
A significantly smaller proportion of patients with pJIA in Study JIA-I treated with tofacitinib 5 mg film-coated tablets twice daily or tofacitinib oral solution weight-based equivalent twice daily flared at Week 44 compared with patients treated with placebo. A significantly greater proportion of patients with pJIA treated with tofacitinib 5 mg film-coated tablets or tofacitinib oral solution achieved JIA ACR30, 50, and 70 responses compared to patients treated with placebo at Week 44 (Table 8).

The occurrence of disease flare and JIA ACR30/50/70 results were favourable to tofacitinib 5 mg twice daily in comparison to placebo across the RF+ polyarthritis, RF- polyarthritis, extended oligoarthritis, and jPsA JIA subtypes and were consistent with those for the overall population.

The occurrence of disease flare and JIA ACR30/50/70 results were favourable to tofacitinib 5 mg twice daily in comparison to placebo for pJIA patients who received tofacitinib 5 mg twice daily with concomitant MTX use on Day 1 [n=101 (76%)] and those who were on tofacitinib monotherapy [n=32 (24%)]. In addition, the occurrence of disease flare and JIA ACR30/50/70 results were also favourable to tofacitinib 5 mg twice daily compared to placebo for pJIA patients who had prior bDMARD experience [n=39 (29%)] and those who were bDMARD naïve [n=94 (71%)].

In Study JIA-I, at Week 2 of the open-label run-in phase, the JIA ACR30 response in patients with pJIA was 45.03%.

Table 8: Primary and secondary efficacy endpoints in patients with pJIA at Week 44* in Study JIA-I (all p-values<0.05)
Primary endpoint                                          Difference (%) (Type I error                         Occurrence        from placebo controlled)         Treatment group      rate            (95% CI)
Occurrence of disease     Tofacitinib 5 mg      28%         -24.7 (-40.8, -8.5) flare                     Twice Daily
(N=67)
Placebo               53%
(N=66)
Secondary endpoints                                          Difference (%) (Type I error                                Response         from placebo controlled)               Treatment group       rate            (95% CI) 
JIA ACR30                       Tofacitinib 5 mg                  72%             24.7 (8.50, 40.8) Twice Daily
(N=67)
Placebo                           47%
(N=66)
JIA ACR50                       Tofacitinib 5 mg                  67%             20.2 (3.72, 36.7) Twice Daily
(N=67)
Placebo                           47%
(N=66)
JIA ACR70                       Tofacitinib 5 mg                  55%             17.4 (0.65, 34.0) Twice Daily
(N=67)
Placebo                           38%
(N=66)
Secondary endpoint                                                               Difference from (Type I error                                                 LS mean           placebo (95% CI) controlled)                      Treatment group               (SEM)
Change from Double-             Tofacitinib 5 mg             -0.11 (0.04)       -0.11 (-0.22, -0.01) Blind Baseline in               Twice Daily
CHAQ Disability                 (N=67; n=46)
Index                           Placebo                        0.00 (0.04) (N=66; n=31)
ACR = American College of Rheumatology; CHAQ = childhood health assessment questionnaire; CI = confidence interval; JIA = juvenile idiopathic arthritis; LS = least squares; n = number of patients with observations at the visit; N = total number of patients; SEM = standard error of the mean * The 26-week double-blind phase is from Week 18 through Week 44 on and after randomisation day.
The Type-I error-controlled endpoints are tested in this order: Disease Flare, JIA ACR50, JIA ACR30, JIA ACR70, CHAQ Disability Index.

In the double-blind phase, each of the components of the JIA ACR response showed greater improvement from the open-label baseline (Day 1) at Week 24 and Week 44 for patients with pJIA treated with tofacitinib oral solution dosed as 5 mg twice daily or weight-based equivalent twice daily compared with those receiving placebo in Study JIA-I.

Physical function and health-related quality of life
Changes in physical function in Study JIA-I were measured by the CHAQ Disability Index. The mean change from the double-blind baseline in CHAQ-Disability Index in patients with pJIA was significantly lower in the tofacitinib 5 mg film-coated tablets twice daily or tofacitinib oral solution weight-based equivalent twice daily compared to placebo at Week 44 (Table 8). The mean change from the double-blind baseline in CHAQ Disability Index results were favourable to tofacitinib 5 mg twice daily in comparison to placebo across the RF+ polyarthritis, RF- polyarthritis, extended oligoarthritis, and jPsA JIA subtypes and were consistent with those for the overall study population.

Long-term controlled safety data in RA

Study ORAL Surveillance (A3921133) was a large (N=4362), randomised active-controlled post-authorisation safety surveillance study of rheumatoid arthritis patients who were 50 years of age and older and had at least one additional cardiovascular risk factor (CV risk factors defined as: current cigarette smoker, diagnosis of hypertension, diabetes mellitus, family history of premature coronary heart disease, history of coronary artery disease including a history of revascularization procedure, coronary artery bypass grafting, myocardial infarction, cardiac arrest, unstable angina, acute coronary syndrome, and presence of extra-articular disease associated with RA, e.g. nodules, Sjögren’s syndrome, anaemia of chronic disease, pulmonary manifestations). The majority (more than 90%) of tofacitinib patients who were current or past smokers had a smoking duration of more than 10 years and a median of 35.0 and 39.0 smoking years, respectively. Patients were required to be on a stable dose of methotrexate at study entry; dose adjustment was permitted during the study.


Patients were randomised to open-label tofacitinib 10 mg twice daily, tofacitinib 5 mg twice daily, or a TNF inhibitor (TNF inhibitor was either etanercept 50 mg once weekly or adalimumab 40 mg every other week) in a 1:1:1 ratio. The co-primary endpoints were adjudicated malignancies excluding NMSC and adjudicated major adverse cardiovascular events (MACE); cumulative incidence and statistical assessment of endpoints were blinded. The study was an event-powered study that also required at least 1500 patients to be followed for 3 years. The study treatment of tofacitinib 10 mg twice daily was stopped and patients were switched to 5 mg twice daily because of a dose-dependent signal of venous thromboembolic events (VTE). For patients in the tofacitinib 10 mg twice daily treatment arm, the data collected before and after the dose switch were analysed in their originally randomised treatment group.

The study did not meet the non-inferiority criterion for the primary comparison of the combined tofacitinib doses to TNF inhibitor since the upper limit of the 95% CI for HR exceeded the pre-specified non-inferiority criterion of 1.8 for adjudicated MACE and adjudicated malignancies excluding NMSC.

The results for adjudicated MACE, adjudicated malignancies excluding NMSC, and selected other events are provided below.

MACE (including myocardial infarction) and venous thromboembolism (VTE) An increase in non-fatal myocardial infarction was observed in patients treated with tofacitinib compared to TNF inhibitor. A dose-dependent increase in VTE events was observed in patients treated with tofacitinib compared to TNF inhibitor (see sections 4.4 and 4.8).

Table 9: Incidence rate and hazard ratio for MACE, myocardial infarction and venous thromboembolism
Tofacitinib 5 mg     Tofacitinib 10 mg All Tofacitinibb    TNF inhibitor twice daily          twice dailya                          (TNFi)
MACEc
IR (95% CI) per 100     0.91 (0.67, 1.21)    1.05 (0.78, 1.38)  0.98 (0.79, 1.19)  0.73 (0.52, 1.01) PY
HR (95% CI) vs TNFi 1.24 (0.81, 1.91)        1.43 (0.94, 2.18)  1.33 (0.91, 1.94) Fatal MIc
IR (95% CI) per 100     0.00 (0.00, 0.07)    0.06 (0.01, 0.18)  0.03 (0.01, 0.09)  0.06 (0.01, 0.17) PY
HR (95% CI) vs TNFi 0.00 (0.00, Inf)         1.03 (0.21, 5.11)  0.50 (0.10, 2.49) Non-fatal MIc
IR (95% CI) per 100     0.37 (0.22, 0.57)    0.33 (0.19, 0.53)  0.35 (0.24, 0.48)  0.16 (0.07, 0.31) PY
HR (95% CI) vs TNFi 2.32 (1.02, 5.30)        2.08 (0.89, 4.86)  2.20 (1.02, 4.75) VTEd
IR (95% CI) per 100     0.33 (0.19, 0.53)    0.70 (0.49, 0.99)  0.51 (0.38, 0.67)  0.20 (0.10, 0.37) PY
HR (95% CI) vs TNFi 1.66 (0.76, 3.63)        3.52 (1.74, 7.12)  2.56 (1.30, 5.05) PEd
IR (95% CI) per 100     0.17 (0.08, 0.33)    0.50 (0.32, 0.74)  0.33 (0.23, 0.46)  0.06 (0.01, 0.17) PY
HR (95% CI) vs TNFi 2.93 (0.79, 10.83)       8.26 (2.49, 27.43) 5.53 (1.70, 18.02) DVTd
IR (95% CI) per 100     0.21 (0.11, 0.38)    0.31 (0.17, 0.51)  0.26 (0.17, 0.38)  0.14 (0.06, 0.29) PY
HR (95% CI) vs TNFi 1.54 (0.60, 3.97)        2.21 (0.90, 5.43)  1.87 (0.81, 4.30) a The tofacitinib 10 mg twice daily treatment group includes data from patients that were switched from tofacitinib 10 mg twice daily to tofacitinib 5 mg twice daily as a result of a study modification.
b Combined tofacitinib 5 mg twice daily and tofacitinib 10 mg twice daily.


 cBased on events occurring on treatment or within 60 days of treatment discontinuation.
dBased on events occurring on treatment or within 28 days of treatment discontinuation.
Abbreviations: MACE = major adverse cardiovascular events, MI = myocardial infarction, VTE = venous thromboembolism, PE = pulmonary embolism, DVT = deep vein thrombosis, TNF = tumour necrosis factor, IR = incidence rate, HR = hazard ratio, CI = confidence interval, PY = patient years, Inf = infinity

The following predictive factors for development of MI (fatal and non-fatal) were identified using a multivariate Cox model with backward selection: age ≥65 years, male, current or past smoking, history of diabetes, and history of coronary artery disease (which includes myocardial infarction, coronary heart disease, stable angina pectoris, or coronary artery procedures) (see sections 4.4 and 4.8).

Malignancies

An increase in malignancies excluding NMSC, particularly lung cancer, lymphoma and an increase in NMSC was observed in patients treated with tofacitinib compared to TNF inhibitor.

Table 10: Incidence rate and hazard ratio for malignanciesa
Tofacitinib 5 mg     Tofacitinib 10 mg                       All Tofacitinibc          TNF inhibitor twice daily          twice dailyb                                                      (TNFi) Malignancies excluding NMSC
IR (95% CI) per 100     1.13 (0.87, 1.45)    1.13 (0.86, 1.45)                       1.13 (0.94, 1.35)         0.77 (0.55, 1.04) PY
HR (95% CI) vs TNFi 1.47 (1.00, 2.18)        1.48 (1.00, 2.19)                       1.48 (1.04, 2.09) Lung cancer
IR (95% CI) per 100     0.23 (0.12, 0.40)    0.32 (0.18, 0.51)                       0.28 (0.19, 0.39)         0.13 (0.05, 0.26) PY
HR (95% CI) vs TNFi 1.84 (0.74, 4.62)        2.50 (1.04, 6.02)                       2.17 (0.95, 4.93) Lymphoma
IR (95% CI) per 100     0.07 (0.02, 0.18)    0.11 (0.04, 0.24)                       0.09 (0.04, 0.17)         0.02 (0.00, 0.10) PY
HR (95% CI) vs TNFi 3.99 (0.45, 35.70)       6.24 (0.75, 51.86)                      5.09 (0.65, 39.78) NMSC
IR (95% CI) per 100     0.61 (0.41, 0.86)    0.69 (0.47, 0.96)                       0.64 (0.50, 0.82)         0.32 (0.18, 0.52) PY
HR (95% CI) vs TNFi 1.90 (1.04, 3.47)        2.16 (1.19, 3.92)                       2.02 (1.17, 3.50) a
For malignancies excluding NMSC, lung cancer, and lymphoma, based on events occurring on treatment or after treatment discontinuation up to the end of the study. For NMSC based on events occurring on treatment or within 28 days of treatment discontinuation.
b The tofacitinib 10 mg twice daily treatment group includes data from patients that were switched from tofacitinib 10 mg twice daily  to tofacitinib 5 mg twice daily as a result of a study modification.
c Combined tofacitinib 5 mg twice daily and tofacitinib 10 mg twice daily.

Abbreviations: NMSC = non melanoma skin cancer, TNF = tumour necrosis factor, IR = incidence rate, HR = hazard ratio, CI = confidence interval, PY = patient years

The following predictive factors for development of malignancies excluding NMSC were identified using a Multivariate Cox model with backward selection: age ≥65 years and current or past smoking (see section 4.4 and 4.8).

Mortality
Increased mortality was observed in patients treated with tofacitinib compared to TNF inhibitors.
Mortality was mainly due to cardiovascular events, infections and malignancies.

Table 11: Incidence rate and hazard ratio for mortalitya
Tofacitinib 5 mg        Tofacitinib 10 mg         All Tofacitinibc       TNF inhibitor twice daily             twice dailyb                                     (TNFi) Mortality (all cause)
IR (95% CI) per 100 PY          0.50 (0.33, 0.74)       0.80 (0.57, 1.09)        0.65 (0.50, 0.82)     0.34 (0.20, 0.54) HR (95% CI) vs TNFi             1.49 (0.81, 2.74)       2.37 (1.34, 4.18)        1.91 (1.12, 3.27) 
Fatal infections
IR (95% CI) per 100 PY       0.08 (0.02, 0.20)       0.18 (0.08, 0.35)        0.13 (0.07, 0.22)     0.06 (0.01, 0.17) HR (95% CI) vs TNFi          1.30 (0.29, 5.79)       3.10 (0.84, 11.45)       2.17 (0.62, 7.62) Fatal CV events
IR (95% CI) per 100 PY       0.25 (0.13, 0.43)       0.41 (0.25, 0.63)        0.33 (0.23, 0.46)     0.20 (0.10, 0.36) HR (95% CI) vs TNFi          1.26 (0.55, 2.88)       2.05 (0.96, 4.39)        1.65 (0.81, 3.34) Fatal Malignancies
IR (95% CI) per 100 PY       0.10 (0.03, 0.23)       0.00 (0.00, 0.08)        0.05 (0.02, 0.12)     0.02 (0.00, 0.11) HR (95% CI) vs TNFi         4.88 (0.57, 41.74)         0 (0.00, Inf)         2.53 (0.30, 21.64) a Based on events occurring on treatment or within 28 days of treatment discontinuation.
b The tofacitinib 10 mg twice daily treatment group includes data from patients that were switched from tofacitinib 10 mg twice daily to tofacitinib 5 mg twice daily as a result of a study modification.
c Combined tofacitinib 5 mg twice daily and tofacitinib 10 mg twice daily.

Abbreviations: TNF = tumor necrosis factor, IR = incidence rate, HR = hazard ratio, CI = confidence interval, PY = patient years, CV = cardiovascular, Inf = infinity

Pharmacokinetic Properties

5.2      Pharmacokinetic properties

The PK profile of tofacitinib is characterised by rapid absorption (peak plasma concentrations are reached within 0.5-1 hour), rapid elimination (half-life of ~3 hours) and dose-proportional increases in systemic exposure. Steady state concentrations are achieved in 24-48 hours with negligible accumulation after twice daily administration.

Absorption and distribution

Tofacitinib is well-absorbed, with an oral bioavailability of 74%. Coadministration of tofacitinib with a high-fat meal resulted in no changes in AUC while Cmax was reduced by 32%. In clinical studies, tofacitinib was administered without regard to meal.

After intravenous administration, the volume of distribution is 87 L. Approximately 40% of circulating tofacitinib is bound to plasma proteins. Tofacitinib binds predominantly to albumin and does not appear to bind to α1-acid glycoprotein. Tofacitinib distributes equally between red blood cells and plasma.

Biotransformation 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 radiolabelled study, more than 65% of the total circulating radioactivity was accounted for by unchanged active substance, with the remaining 35% attributed to 8 metabolites, each accounting for less than 8% of total radioactivity. All metabolites have been observed in animal species and are predicted to have less than 10-fold potency than tofacitinib for JAK1/3 inhibition. No evidence of stereo conversion in human samples was detected.
The pharmacologic activity of tofacitinib is attributed to the parent molecule. In vitro, tofacitinib is a substrate for MDR1, but not for breast cancer resistance protein (BCRP), OATP1B1/1B3, or OCT1/2.

Renal impairment

Subjects with mild (creatinine clearance 50-80 mL/min), moderate (creatinine clearance 30-49 mL/min), and severe (creatinine clearance < 30 mL/min) renal impairment had 37%, 43% and 123% higher AUC, respectively, compared to subjects with normal renal function (see section 4.2). In subjects with end-stage renal disease (ESRD), contribution of dialysis to the total clearance of tofacitinib was relatively small. Following a single dose of 10 mg, mean AUC in subjects with ESRD based on concentrations measured on a non-dialysis day was approximately 40% (90% confidence intervals: 1.5-95%) higher compared to subjects with normal renal function. In clinical studies, tofacitinib was not evaluated in patients with baseline creatinine clearance values (estimated by Cockcroft-Gault equation) less than 40 mL/min (see section 4.2).


Hepatic impairment
Subjects with mild (Child Pugh A) and moderate (Child Pugh B) hepatic impairment had 3%, and 65% higher AUC, respectively, compared to subjects with normal hepatic function. In clinical studies, tofacitinib was not evaluated in subjects with severe (Child Pugh C) hepatic impairment (see sections 4.2 and 4.4), or in patients screened positive for hepatitis B or C.

Interactions

Tofacitinib is not an inhibitor or inducer of CYPs (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) and is not an inhibitor of UGTs (UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7). Tofacitinib is not an inhibitor of MDR1, OATP1B1/1B3, OCT2, OAT1/3, or MRP at clinically meaningful concentrations.

Pharmacokinetics in paediatric patients with juvenile idiopathic arthritis Population PK analysis based on results from both tofacitinib 5 mg film-coated tablets twice daily and tofacitinib oral solution weight-based equivalent twice daily indicated that tofacitinib clearance and volume of distribution both decreased with decreasing body weight in JIA patients. The available data indicated that there were no clinically relevant differences in tofacitinib exposure (AUC), based on age, race, gender, patient type or baseline disease severity. The between-subject variability (% coefficient of variation) in (AUC) was estimated to be approximately 24%.