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Actemra (Tocilizumab) - Description and Clinical Pharmacology

 
 



DESCRIPTION

ACTEMRA (tocilizumab) is a recombinant humanized anti-human interleukin 6 (IL-6) receptor monoclonal antibody of the immunoglobulin IgG1κ (gamma 1, kappa) subclass with a typical H2L2 polypeptide structure. Each light chain and heavy chain consists of 214 and 448 amino acids, respectively. The four polypeptide chains are linked intra- and inter-molecularly by disulfide bonds. ACTEMRA has a molecular weight of approximately 148 kDa.

ACTEMRA is supplied as a sterile, preservative-free solution for intravenous (IV) infusion at a concentration of 20 mg/mL. ACTEMRA is a colorless to pale yellow liquid, with a pH of about 6.5. Single-use vials are available containing 80 mg/4 mL, 200 mg/10 mL, or 400 mg/20 mL of ACTEMRA. Injectable solutions of ACTEMRA are formulated in an aqueous solution containing disodium phosphate dodecahydrate and sodium dihydrogen phosphate dehydrate (as a 15 mmol/L phosphate buffer), polysorbate 80 (0.5 mg/mL), and sucrose (50 mg/mL).

CLINICAL PHARMACOLOGY

Mechanism of Action

Tocilizumab binds specifically to both soluble and membrane-bound IL-6 receptors (sIL-6R and mIL-6R), and has been shown to inhibit IL-6-mediated signaling through these receptors. IL-6 is a pleiotropic pro-inflammatory cytokine produced by a variety of cell types including T- and B-cells, lymphocytes, monocytes and fibroblasts. IL-6 has been shown to be involved in diverse physiological processes such as T-cell activation, induction of immunoglobulin secretion, initiation of hepatic acute phase protein synthesis, and stimulation of hematopoietic precursor cell proliferation and differentiation. IL-6 is also produced by synovial and endothelial cells leading to local production of IL-6 in joints affected by inflammatory processes such as rheumatoid arthritis.

Pharmacodynamics

In clinical studies with the 4 mg/kg and 8 mg/kg doses of ACTEMRA, decreases in levels of C-reactive protein (CRP) to within normal ranges were seen as early as week 2. Changes in pharmacodynamic parameters were observed (i.e., decreases in rheumatoid factor, erythrocyte sedimentation rate, serum amyloid A and increases in hemoglobin) with both doses, however the greatest improvements were observed with 8 mg/kg ACTEMRA.

In healthy subjects administered ACTEMRA in doses from 2 to 28 mg/kg, absolute neutrophil counts decreased to the nadir 3 to 5 days following ACTEMRA administration. Thereafter, neutrophils recovered towards baseline in a dose dependent manner. Rheumatoid arthritis patients demonstrated a similar pattern of absolute neutrophil counts following ACTEMRA administration [see Warnings and Precautions].

Pharmacokinetics

The pharmacokinetics characterized in healthy subjects and RA patients suggested that PK is similar between the two populations. The clearance (CL) of tocilizumab decreased with increased doses. At the 10 mg/kg single dose in RA patients, mean CL was 0.29 0.10 mL/hr/kg and mean apparent terminal t1/2 was 151 59 hours (6.3 days).

The pharmacokinetics of tocilizumab were determined using a population pharmacokinetic analysis of 1793 rheumatoid arthritis patients treated with ACTEMRA 4 and 8 mg/kg every 4 weeks for 24 weeks.

The pharmacokinetic parameters of tocilizumab did not change with time. A more than dose-proportional increase in area under the curve (AUC) and trough concentration (Cmin) was observed for doses of 4 and 8 mg/kg every 4 weeks. Maximum concentration (Cmax) increased dose-proportionally. At steady-state, predicted AUC and Cmin were 2.7 and 6.5-fold higher at 8 mg/kg as compared to 4 mg/kg, respectively.

For doses of ACTEMRA 4 mg/kg given every 4 weeks, the predicted mean ( SD) steady-state AUC, Cmin and Cmax of tocilizumab were 13000 5800 mcg•h/mL, 1.49 2.13 mcg/mL, and 88.3 41.4 mcg/mL, respectively. The accumulation ratios for AUC and Cmax were 1.11 and 1.02, respectively. The accumulation ratio was higher for Cmin (1.96). Steady-state was reached following the first administration for Cmax and AUC, respectively, and after 16 weeks Cmin.

For doses of ACTEMRA 8 mg/kg given every 4 weeks, the predicted mean ( SD) steady-state AUC, Cmin and Cmax of tocilizumab were 35000 15500 mcg•h/mL, 9.74 10.5 mcg/mL, and 183 85.6 mcg/mL, respectively. The accumulation ratios for AUC and Cmax were 1.22 and 1.06, respectively. The accumulation ratio was higher for Cmin (2.35). Steady-state was reached following the first administration and after 8 and 20 weeks for Cmax, AUC, and Cmin, respectively. Tocilizumab AUC, Cmin and Cmax increased with increase of body weight. At body weight ≥ 100 kg, the predicted mean ( SD) steady-state AUC, Cmin and Cmax of tocilizumab were 55500 14100 mcg•h/mL, 19.0 12.0 mcg/mL, and 269 57 mcg/mL, respectively, which are higher than mean exposure values for the patient population. Therefore, ACTEMRA doses exceeding 800 mg per infusion are not recommended [see Dosage and Administration].

Distribution

Following intravenous dosing, tocilizumab undergoes biphasic elimination from the circulation. In rheumatoid arthritis patients the central volume of distribution was 3.5 L and the peripheral volume of distribution was 2.9 L, resulting in a volume of distribution at steady state of 6.4 L.

Elimination

The total clearance of tocilizumab is concentration-dependent and is the sum of the linear clearance and the nonlinear clearance. The linear clearance was estimated to be 12.5 mL/h in the population pharmacokinetic analysis. The concentration-dependent nonlinear clearance plays a major role at low tocilizumab concentrations. Once the nonlinear clearance pathway is saturated, at higher tocilizumab concentrations, clearance is mainly determined by the linear clearance.

The t1/2 of tocilizumab is concentration-dependent. The concentration-dependent apparent t1/2 is up to 11 days for 4 mg/kg and up to 13 days for 8 mg/kg every 4 weeks at steady-state.

Pharmacokinetics in Special Populations

Population pharmacokinetic analyses in adult rheumatoid arthritis patients showed that age, gender and race did not affect the pharmacokinetics of tocilizumab. Linear clearance was found to increase with body size. The body weight-based dose (8 mg/kg) resulted in approximately 86% higher exposure in patients who are greater than 100 kg in comparison to patients who are less than 60 kg.

Hepatic Impairment

No formal study of the effect of hepatic impairment on the pharmacokinetics of tocilizumab was conducted.

Renal Impairment

No formal study of the effect of renal impairment on the pharmacokinetics of tocilizumab was conducted.

Most patients in the population pharmacokinetic analysis had normal renal function or mild renal impairment. Mild renal impairment (creatinine clearance < 80 mL/min and ≥ 50 mL/min based on Cockcroft-Gault) did not impact the pharmacokinetics of tocilizumab. No dose adjustment is required in patients with mild renal impairment.

Drug Interactions

In vitro data suggested that IL-6 reduced mRNA expression for several CYP450 isoenzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, and this reduced expression was reversed by co-incubation with tocilizumab at clinically relevant concentrations. Accordingly, inhibition of IL-6 signaling in RA patients treated with tocilizumab may restore CYP450 activities to higher levels than those in the absence of tocilizumab leading to increased metabolism of drugs that are CYP450 substrates. Its effect on CYP2C8 or transporters (e.g., P-gp) is unknown. This is clinically relevant for CYP450 substrates with a narrow therapeutic index, where the dose is individually adjusted. Upon initiation of ACTEMRA, in patients being treated with these types of medicinal products, therapeutic monitoring of the effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) should be performed and the individual dose of the medicinal product adjusted as needed. Caution should be exercised when ACTEMRA is coadministered with drugs where decrease in effectiveness is undesirable, e.g., oral contraceptives (CYP3A4 substrates) [see Drug Interactions].

Simvastatin

Simvastatin is a CYP3A4 and OATP1B1 substrate. In 12 RA patients, not treated with ACTEMRA, receiving 40 mg simvastatin, exposures of simvastatin and its metabolite, simvastatin acid, was 4- to 10-fold and 2-fold higher, respectively, than the exposures observed in healthy subjects. One week following administration of a single infusion of ACTEMRA (10 mg/kg), exposure of simvastatin and simvastatin acid decreased by 57% and 39%, respectively, to exposures that were similar or slightly higher than those observed in healthy subjects. Exposures of simvastatin and simvastatin acid increased upon withdrawal of ACTEMRA in RA patients. Selection of a particular dose of simvastatin in RA patients should take into account the potentially lower exposures that may result after initiation of ACTEMRA (due to normalization of CYP3A4) or higher exposures after discontinuation of ACTEMRA.

Omeprazole

Omeprazole is a CYP2C19 and CYP3A4 substrate. In RA patients receiving 10 mg omeprazole, exposure to omeprazole was approximately 2 fold higher than that observed in healthy subjects. In RA patients receiving 10 mg omeprazole, before and one week after ACTEMRA infusion (8 mg/kg), the omeprazole AUCinf decreased by 12% for poor (N=5) and intermediate metabolizers (N=5) and by 28% for extensive metabolizers (N=8) and were slightly higher than those observed in healthy subjects.

Dextromethorphan

Dextromethorphan is a CYP2D6 and CYP3A4 substrate. In 13 RA patients receiving 30 mg dextromethorphan, exposure to dextromethorphan was comparable to that in healthy subjects. However, exposure to its metabolite, dextrorphan (a CYP3A4 substrate), was a fraction of that observed in healthy subjects. One week following administration of a single infusion of ACTEMRA (8 mg/kg), dextromethorphan exposure was decreased by approximately 5%. However, a larger decrease (29%) in dextrorphan levels was noted after ACTEMRA infusion.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis. No long-term animal studies have been performed to establish the carcinogenicity potential of tocilizumab.

Mutagenesis. Tocilizumab was negative in the in vitro Ames bacterial reverse mutation assay and the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes.

Impairment of Fertility. Fertility studies conducted in male and female mice using a murine analogue of tocilizumab showed no impairment of fertility.

CLINICAL STUDIES

The efficacy and safety of ACTEMRA was assessed in five randomized, double-blind, multicenter studies in patients > 18 years with active rheumatoid arthritis diagnosed according to American College of Rheumatology (ACR) criteria. Patients had at least 8 tender and 6 swollen joints at baseline. ACTEMRA was given intravenously every 4 weeks as monotherapy (Study I), in combination with methotrexate (MTX) (Studies II and III) or other disease-modifying anti-rheumatic drugs (DMARDs) (Study IV) in patients with an inadequate response to those drugs, or in combination with MTX in patients with an inadequate response to TNF antagonists (Study V).

Study I evaluated patients with moderate to severe active rheumatoid arthritis who had not been treated with MTX within 6 months prior to randomization, or who had not discontinued previous methotrexate treatment as a result of clinically important toxic effects or lack of response. In this study, 67% of patients were MTX-naive, and over 40% of patients had rheumatoid arthritis < 2 years. Patients received ACTEMRA 8 mg/kg monotherapy or MTX alone (dose titrated over 8 weeks from 7.5 mg to a maximum of 20 mg weekly). The primary endpoint was the proportion of ACTEMRA patients who achieved an ACR20 response at Week 24.

Study II is an ongoing 2-year study with a planned interim analysis at week 24 that evaluated patients with moderate to severe active rheumatoid arthritis who had an inadequate clinical response to MTX. Patients received ACTEMRA 8 mg/kg, ACTEMRA 4 mg/kg, or placebo every four weeks, in combination with MTX (10 to 25 mg weekly). The primary endpoint at week 24 was the proportion of patients who achieved an ACR20 response.

Study III evaluated patients with moderate to severe active rheumatoid arthritis who had an inadequate clinical response to MTX. Patients received ACTEMRA 8 mg/kg, ACTEMRA 4 mg/kg, or placebo every four weeks, in combination with MTX (10 to 25 mg weekly). The primary endpoint was the proportion of patients who achieved an ACR20 response at week 24.

Study IV evaluated patients who had an inadequate response to their existing therapy, including one or more DMARDs. Patients received ACTEMRA 8 mg/kg or placebo every four weeks, in combination with the stable DMARDs. The primary endpoint was the proportion of patients who achieved an ACR20 response at week 24.

Study V evaluated patients with moderate to severe active rheumatoid arthritis who had an inadequate clinical response or were intolerant to one or more TNF antagonist therapies. The TNF antagonist therapy was discontinued prior to randomization. Patients received ACTEMRA 8 mg/kg, ACTEMRA 4 mg/kg, or placebo every four weeks, in combination with MTX (10 to 25 mg weekly). The primary endpoint was the proportion of patients who achieved an ACR20 response at week 24.

Clinical Response

The percentages of ACTEMRA-treated patients achieving ACR20, 50 and 70 responses are shown in Table 3. In all studies, patients treated with 8 mg/kg ACTEMRA had statistically significant ACR20, ACR50, and ACR70 response rates versus MTX- or placebo-treated patients at week 24.

Patients treated with ACTEMRA at a dose of 4 mg/kg in patients with inadequate response to DMARDs or TNF antagonist therapy had lower response rates compared to patients treated with ACTEMRA 8 mg/kg.

Table 3 ACR Response at 6 Months in Active and Placebo Controlled Trials (Percent of Patients)
Percent of Patients

Response Rate Week 24
Study I Study II Study III Study IV Study V
MTX ACTEMRA 8 mg/kg Placebo + MTX ACTEMRA 4 mg/kg + MTX ACTEMRA 8 mg/kg + MTX Placebo + MTX ACTEMRA 4 mg/kg + MTX ACTEMRA 8 mg/kg + MTX Placebo + DMARDs ACTEMRA 8 mg/kg + DMARDs Placebo + MTX ACTEMRA 4 mg/kg + MTX ACTEMRA 8 mg/kg + MTX
N=284 N=286 N=393 N=399 N=398 N=204 N=213 N=205 N=413 N=803 N=158 N=161 N=170
ACR20
Responders 53% 70% 27% 51% 56% 27% 48% 59% 25% 61% 10% 30% 50%
Weighted Difference % 1
(95% CI) 2
19
(11, 27)
23
(17, 29)
29
(23, 35)
23
(15, 32)
32
(23, 41)
35
(30, 40)
25
(15, 36)
46
(36, 56)
ACR50
Responders 34% 44% 10% 25% 32% 11% 32% 44% 9% 38% 4% 17% 29%
Weighted Difference %
(95% CI)
12
(4, 20)
15
(9, 20)
22
(16, 28)
21
(13, 29)
33
(25, 41)
28
(23, 33)
15
(5, 25)
31
(21, 41)
ACR70
Responders 15% 28% 2% 11% 13% 2% 12% 22% 3% 21% 1% 5% 12%
Weighted Difference %
(95% CI)
14
(7, 22)
8
(3, 13)
10
(5, 15)
11
(4, 18)
20
(12, 27)
17
(13, 21)
4
(-6, 13)
12
(3, 22)

1 The weighted difference is the difference between ACTEMRA and Placebo response rates, adjusted for site (and disease duration for Study I only).
2 CI: 95% confidence interval of the weighted difference

The results of the components of the ACR response criteria for Studies III and V are shown in Table 4. Similar results to Study III were observed in Studies I, II and IV.

Table 4 Components of ACR Response at 6 Months
Study III Study V
ACTEMRA 4 mg/kg + MTX ACTEMRA 8 mg/kg + MTX Placebo + MTX ACTEMRA 4 mg/kg + MTX ACTEMRA 8 mg/kg + MTX Placebo + MTX
N=213 N=205 N=204 N=161 N=170 N=158
Component (mean) Baseline Week 24 1 Baseline Week 24 Baseline Week 24 Baseline Week 24 Baseline Week 24 Baseline Week 24
Number of tender joints (0-68) 33 19
-7.0
(-10.0, -4.1)
32 14.5
-9.6
(-12.6, -6.7)
33 25 31 21
-10.8
(-14.6, -7.1)
32 17
-15.1
(-18.8, -11.4)
30 30
Number of swollen joints (0-66) 20 10
-4.2
(-6.1, -2.3)
19.5 8
-6.2
(-8.1, -4.2)
21 15 19.5 13
-6.2
(-9.0, -3.5)
19 11
-7.2
(-9.9, -4.5)
19 18
Pain 2 61 33
-11.0
(-17.0, -5.0)
60 30
-15.8
(-21.7, -9.9)
57 43 63.5 43
-12.4
(-22.1, -2.1)
65 33
-23.9
(-33.7, -14.1)
64 48
Patient global assessment 66 34
-10.9
(-17.1, -4.8)
65 31
-14.9
(-20.9, -8.9)
64 45 70 46
-10.0
(-20.3, 0.3)
70 36
-17.4
(-27.8, -7.0)
71 51
Physician global assessment 64 26
-5.6
(-10.5, -0.8)
64 23
-9.0
(-13.8, -4.2)
64 32 66.5 39
-10.5
(-18.6, -2.5)
66 28
-18.2
(-26.3, -10.0)
67.5 43
Disability index (HAQ)Health Assessment Questionnaire: 0 = best, 3 = worst; 20 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities 1.64 1.01
-0.18
(-0.34, -0.02)
1.55 0.96
-0.21
(-0.37, -0.05)
1.55 1.21 1.67 1.39
-0.25
(-0.42, -0.09)
1.75 1.34
-0.34
(-0.51, -0.17)
1.70 1.58
CRP (mg/dL) 2.79 1.17
-1.30
(-2.0, -0.59)
2.61 0.25
-2.156
(-2.86, -1.46)
2.36 1.89 3.11 1.77
-1.34
(-2.5, -0.15)
2.80 0.28
-2.52
(-3.72, -1.32)
3.705 3.06

1 Data shown is mean at week 24, difference in adjusted mean change from baseline compared with placebo + MTX at week 24 and 95% confidence interval for that difference
2 Visual analog scale: 0 = best, 100 = worst

The percent of ACR20 responders by visit for Study III is shown in Figure 1. Similar responses were observed in studies I, II, IV, and V.

Figure 1 Percent of ACR20 Responders by Visit for Study III (Inadequate Response to MTX)The same patients may not have responded at each timepoint.

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