XELJANZ / XELJANZ XR (tofacitinib) Action And Clinical Pharmacology

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Mechanism of Action

Tofacitinib is a potent, selective inhibitor of the JAK family of kinases with a high degree of selectivity against other kinases in the human genome. In kinase assays, tofacitinib, inhibits JAK1, JAK2, JAK3, and to a lesser extent TyK2. In cellular settings where JAK kinases signal in pairs, tofacitinib preferentially inhibits signaling by heterodimeric receptors associated with JAK3 and/or JAK1 with functional selectivity over receptors that signal via pairs of JAK2. Inhibition of JAK1 and JAK3 by tofacitinib blocks signaling through the common gamma chain-containing receptors for several cytokines, including IL-2, -4,-7,-9, -15, and -21. These cytokines are integral to lymphocyte activation, proliferation, and function and inhibition of their signaling may thus result in modulation of multiple aspects of the immune response. In addition, inhibition of JAK1 will result in attenuation of signaling by additional pro-inflammatory cytokines, such as IL-6 and Type I interferons. At higher exposures, inhibition of erythropoietin signaling could occur via inhibition of JAK2 signaling.

Pharmacodynamics

In patients with RA, treatment with XELJANZ (tofacitinib) 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 were small and inconsistent. The clinical significance of these changes is unknown.

Changes in total serum IgG, M, and A levels over 6-month dosing of patients with RA were small, not dose-dependent and similar to those seen on placebo.

After treatment with XELJANZ in patients with RA, 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 half-life.

Similar changes in T cells, B cells and serum CRP have been observed in patients with active PsA, although reversibility was not assessed. Total serum immunoglobulins were not assessed in patients with active PsA.

Patients with UC were not studied.

Pharmacokinetics (PK)

XELJANZ

Following oral administration of XELJANZ, the PK profile of XELJANZ is characterized 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 in the therapeutic dose range. Steady state concentrations are achieved in 24-48 hours with negligible accumulation after BID administration.

A geometric mean accumulation ratio (Rac) of 1.12 following BID dosing indicates little difference between single dose and steady state concentrations as well as the predictability of steady state PK from single dose data. The dose-AUC relationship was adequately described by a linear model fit to log-both sides transformed data while the dose - Cmax relationship were best described by a nonlinear sigmoidal, hyperbolic model fit to log-transformed Cmax data. Although the nonlinear model provided better description of the dose - Cmax relationship relative to a linear model, when compared to 5 mg, the mean model predicted relative changes in dose-normalized Cmax were approximately +7% for 10 mg, +2% for 30 mg, and -10% for 50 mg doses. These small changes from linearity support the conclusion that XELJANZ Cmax is approximately dose proportional at least up to 5 times the 10 mg dose.

XELJANZ XR

Following oral administration of XELJANZ XR, peak plasma tofacitinib concentrations are reached at 4 hours and the half‑life is ~6 hours. Steady state concentrations are achieved within 48 hours with negligible accumulation (accumulation ratio: 1.12) after once daily (QD) administration. At steady state, Cmin for XELJANZ XR 11 mg QD is approximately 29% lower and Ctrough is approximately 26% lower compared to XELJANZ 5 mg BID. Area under the curve (AUC) and Cmax of tofacitinib for XELJANZ XR 11 mg administered once daily are equivalent to those of XELJANZ 5 mg administered twice daily.

Pharmacokinetics in Patients with Moderately to Severely Active UC

Population PK analysis in UC patients indicated that PK characteristics were similar to that of RA patients. There were no clinically relevant differences in tofacitinib exposure (AUC), based on age, weight, gender and race, after accounting for differences in renal function (i.e., creatinine clearance) between patients. The between-subject variability (% coefficient of variation) in AUC of tofacitinib is estimated to be approximately 23% to 25% in UC patients.

Absorption:

XELJANZ

Tofacitinib is well-absorbed, with an absolute oral bioavailability of 74% following administration of XELJANZ. 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 meal.

XELJANZ XR

Coadministration of XELJANZ XR with a high-fat meal resulted in no changes in AUC while Cmax was increased by 27% and Tmax was extended by approximately 1 hour.

Distribution:

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 α1-acid glycoprotein. Tofacitinib distributes equally between red blood cells and plasma.

Metabolism:

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.

Excretion:

Approximately 94% of a radioactive dose of XELJANZ was recovered from the urine (80%) and feces (14%), with the majority of excreted radioactivity recovered within 24 hours after dosing.

Table 8: Summary of Tofacitinib Pharmacokinetic Parameters after Repeated Oral Administration of XELJANZ 10 mg BID or Single IV Administration in Humans
 
N/A = Not available; Cmax = maximum plasma concentration; t½ = terminal elimination half-life; AUC0-12 = area under the plasma concentration-time curve from time 0 to 12 hours post dose; CL = total systemic clearance; Vss = volume of distribution at steady state

Oral Administration

IV Administration

Cmax

(ng/mL)

t½

(h)

AUC0-12hrs

(ng·h/mL)

Clearance

(L/h)

Volume of distribution (L)

Healthy Volunteers

79.4

3.0

311

25

87

RA Patients

116

3.62

507

N/A

(no IV data)

N/A

(no IV data)

PsA Patients

88.9

3.74

436

N/A

(no IV data)

N/A

(no IV data)

UC Patients

91

3.05

404

N/A

(no IV data)

N/A

(no IV data)

Table 9: Summary of Tofacitinib Pharmacokinetic Parameters after Repeated Oral Administration of XELJANZ XR 11 mg QD in Humans
 
Cmax = maximum plasma concentration; t½ = terminal elimination half-life; AUC0-24 = area under the plasma concentration-time curve from time 0 to 24 hours post dose
 

Cmax

(ng/mL)

t½

(h)

AUC0-24hrs

(ng·h/mL)

Tmax (h)

Healthy Volunteers

38.23

5.89

269

4.0

Special Populations and Conditions

Rheumatoid Arthritis and Ulcerative Colitis

Pediatrics (< 18 years of age):

The pharmacokinetics, safety and effectiveness of tofacitinib in pediatric patients have not been established; therefore, XELJANZ/XELJANZ XR should not be used in this patient population. Pharmacokinetic of tofacitinib was characterized in an open-label, non-randomized, multi-center, Phase 1 study conducted in pediatric patients (aged from 2 to less than 18 years) with juvenile idiopathic arthritis. A total of 26 patients were enrolled in this study and treated at dosing regimens based on the children’s age and body weight. The study consisted of 3 cohorts based on subject age with at least 8 subjects per cohort. Based on limited data, the PK profile of tofacitinib appears to be characterized by a rapid absorption (peak plasma concentrations were reached within 0.5-1 hour) and a rapid elimination. The average half-lives for tofacitinib were approximately 2.6h, 1.9h, and 1.8h for the Cohorts 1 (12 to <18 years), 2 (6 to <12 years) and 3 (2 to <6 years), respectively, with individual values ranging from 1.4 to 3.1h across all cohorts.

Geriatrics (>65 years of age):

Population PK analysis in RA patients indicated that elderly patients 80 years of age were estimated to have <5% higher XELJANZ AUC relative to the mean age of 55 years. Of the 3315 patients who enrolled in studies I to V, a total of 505 (15%) RA patients were 65 years of age and older, including 71 (2%) patients 75 years and older. The frequency of serious infection among XELJANZ treated subjects 65 years of age and older was higher than those under the age of 65.

There were not enough elderly patients treated with XELJANZ (n=77) in the UC program to adequately study the effects of XELJANZ in this population. As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly (see WARNINGS AND PRECAUTIONS).

Gender :

Based on population PK analysis, female RA patients were estimated to have 7% lower XELJANZ AUC compared to male RA patients. Female UC patients were estimated to have 15.2% higher XELJANZ AUC compared to male UC patients.

Race :

In RA patients, no major differences (<5%) were estimated in XELJANZ AUC between White, Black and Asian RA patients by population PK analysis. In UC patients, population PK analysis indicated that Asian patients had 7.3% higher XELJANZ AUC compared to non-Asian patients. There was a higher incidence of adverse events in Asian patients. Therefore, XELJANZ/XELJANZ XR should be used with caution in Asian patients (see WARNINGS AND PRECAUTIONS).

Body Weight :

Population PK analysis in RA patients indicated that systemic exposure (AUC) of XELJANZ in the extremes of body weight (40 kg, 140 kg) were similar to that of a 70 kg patient. 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 XELJANZ is estimated to be approximately 27%. Population PK analysis in UC patients also indicated that XELJANZ AUC did not significantly change with patient body weight.

Hepatic Impairment:

XELJANZ/XELJANZ XR is contraindicated in patients with severe hepatic impairment (see CONTRAINDICATIONS). Subjects with mild and moderate hepatic impairment had 3%, and 65% higher XELJANZ AUC, respectively, compared with healthy subjects.

No dose adjustment of XELJANZ/XELJANZ XR is required in patients with mild hepatic impairment. XELJANZ XR has not been studied in patients with moderate and severe hepatic impairment. Therefore, XELJANZ XR should not be used in patients with moderate hepatic impairment.

The recommended total daily dose in patients with moderate hepatic impairment is half the total daily dose recommended for patients with normal hepatic function. The recommended dose is XELJANZ 5 mg twice daily when the indicated dose in the presence of normal hepatic function is XELJANZ 10 mg twice daily; the recommended dose is XELJANZ 5 mg once daily when the indicated dose in the presence of normal hepatic function is XELJANZ 5 mg twice daily (see DOSAGE AND ADMINISTRATION).

XELJANZ/XELJANZ XR has not been studied in patients with severe hepatic impairment or in patients with positive hepatitis B virus or hepatitis C virus serology, and should not be used in these populations.

Renal Impairment:

Subjects with mild, moderate, and severe renal impairment had 37%, 43% and 123% higher XELJANZ AUC, respectively, compared with healthy subjects. In subjects with end-stage renal disease (ESRD) undergoing hemodialysis, the contribution of dialysis to the total clearance of tofacitinib was relatively small.

In subjects with ESRD undergoing hemodialysis, mean AUC was approximately 40% higher compared with historical healthy subject data, consistent with approximately 30% contribution of renal clearance to the total clearance of tofacitinib. Dose adjustment is recommended in ESRD patients undergoing hemodialysis (see DOSAGE AND ADMINISTRATION).

No dose adjustment of XELJANZ/XELJANZ XR is required in patients with mild renal impairment. XELJANZ XR has not been studied in patients with moderate and severe renal impairment. Therefore, XELJANZ XR is not recommended in patients with moderate and severe renal impairment, including patients with ESRD undergoing hemodialysis.

The recommended total daily dose in patients with moderate or severe renal impairment, including patients with ESRD but not limited to those undergoing hemodialysis undergoing, is half the total daily dose recommended for patients with normal renal function. The recommended dose is XELJANZ 5 mg twice daily when the indicated dose in the presence of normal renal function is XELJANZ 10 mg twice daily; the recommended dose is XELJANZ 5 mg once daily when the indicated dose in the presence of normal renal function is XELJANZ 5 mg twice daily (see DOSAGE AND ADMINISTRATION).

In clinical trials, XELJANZ/XELJANZ XR was not evaluated in patients with baseline creatinine clearance values (estimated by the Cockroft-Gault equation) less than 40 mL/min.

Genetic Polymorphism:

Mean Cmax and AUC0-∞ values of tofacitinib following administration of XELJANZ in poor metabolizers of CYP2C19 (carriers of CYP2C19*2/*2, CYP2C19*2/*3 or CYP2C19*3/*3 alleles) were approximately 15% and 17% greater, respectively, than those in normal metabolizers, indicating that CYP2C19 is a minor contributor of XELJANZ clearance.

The impact of intrinsic factors on tofacitinib following administration of XELJANZ pharmacokinetics is summarized in Figure 3 with dosage adjustment recommendations.

Figure 3: Impact of Intrinsic Factors on Tofacitinib Pharmacokinetics

 
PK=Pharmacokinetics; CI=Confidence Interval
 
Note: 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.
a
In RA patients the recommended dose is XELJANZ 5 mg once daily. In UC patients the recommended dose is half the total daily dose indicated for patients with normal renal and hepatic function, i.e, the recommended dose is XELJANZ 5 mg twice daily when the indicated dose in the presence of normal renal and hepatic function is XELJANZ 10 mg twice daily, and the recommended dose is XELJANZ 5 mg once daily when the indicated dose in the presence of normal renal and hepatic function is XELJANZ 5 mg twice daily.
b
Supplemental doses are not necessary in patients after dialysis.

Psoriatic Arthritis

Results from population PK analysis in patients with active PsA were consistent with those in patients with RA.