Tocilizumab binds specifically to both soluble and membrane-bound IL-6 receptors (sIL-6R and mIL-6R). Tocilizumab has been shown to inhibit sIL-6R and mIL-6R-mediated signalling. IL-6 is a pleiotropic pro-inflammatory cytokine produced by a variety of cell types including T- and B-cells, monocytes and fibroblasts. IL-6 is involved in diverse physiological processes such as T-cell activation, induction of immunoglobulin secretion, induction of hepatic acute phase protein synthesis and stimulation of haemopoiesis. IL-6 has been implicated in the pathogenesis of diseases including inflammatory diseases, osteoporosis and neoplasia.
In clinical trials with tocilizumab, rapid decreases in CRP, erythrocyte sedimentation rate (ESR), serum amyloid A (SAA) and fibrinogen were observed. Consistent with the effect on acute phase reactants, treatment with tocilizumab was associated with reduction in platelet count within the normal range. Increases in haemoglobin levels were observed, through tocilizumab decreasing the IL-6 driven effects on hepcidin production to increase iron availability. In treated patients, decreases in the levels of CRP to within normal ranges were seen as early as week 2, with decreases maintained while on treatment.
In GCA clinical study WA28119, similar rapid decreases in CRP and ESR were observed along with slight increases in mean corpuscular haemoglobin concentration. In healthy subjects administered tocilizumab in doses from 2 to 28 mg/kg intravenously and 81 to 162 mg subcutaneously, absolute neutrophil counts decreased to their lowest 2 to 5 days following administration. Thereafter, neutrophils recovered towards baseline in a dose dependent manner.
Patients demonstrate a comparable (to healthy subjects) decrease of absolute neutrophil counts following tocilizumab administration.
In COVID-19 patients with one dose of tocilizumab 8 mg/kg administered intravenously, decreases in the levels of CRP to within normal ranges were seen as early as day 7.
The pharmacokinetics of tocilizumab is characterised by nonlinear elimination which is a combination of linear clearance and Michaelis-Menten elimination. The nonlinear part of elimination leads to an increase in exposure that is more than dose-proportional. The pharmacokinetic parameters of tocilizumab do not change with time. Due to the dependence of total clearance on tocilizumab serum concentrations, the half-life of tocilizumab is also concentration-dependent and varies depending on the serum concentration level. Population pharmacokinetic analyses in any patient population tested so far indicate no relationship between apparent clearance and the presence of anti-drug antibodies.
The pharmacokinetics of tocilizumab were determined using a population pharmacokinetic analysis on a database composed of 3552 RA patients treated with a one-hour infusion of 4 or 8 mg/kg tocilizumab every 4 weeks for 24 weeks or with 162 mg tocilizumab given subcutaneously either once a week or every other week for 24 weeks.
The following parameters (predicted mean ± SD) were estimated for a dose of 8 mg/kg tocilizumab given every 4 weeks: steady-state area under curve (AUC) = 38000 ± 13000 h μg/mL, trough concentration (Cmin) = 15.9 ± 13.1 μg/mL and maximum concentration (Cmax) = 182 ± 50.4 μg/mL, and. the accumulation ratios for AUC and Cmax were small, 1.32 and 1.09, respectively. The accumulation ratio was higher for Cmin (2.49), which was expected based on the non-linear clearance contribution at lower concentrations. Steady-state was reached following the first administration for Cmax and after 8 and 20 weeks for 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 50000 ± 16800 μg•h/mL, 24.4 ± 17.5 μg/mL, and 226 ± 50.3 μg/mL, respectively, which are higher than mean exposure values for the patient population (i.e. all body weights) reported above. The dose-response curve for tocilizumab flattens at higher exposure, resulting in smaller efficacy gains for each incremental increase in concentration such that clinically meaningful increases in efficacy were not demonstrated in patients treated with >800 mg of tocilizumab. Therefore, doses exceeding 800 mg per infusion are not recommended.
In RA patients the central volume of distribution was 3.72, the peripheral volume of distribution was 3.35 resulting in a volume of distribution at steady-state of 7.07.
Following intravenous administration, tocilizumab undergoes biphasic elimination from the circulation. The total clearance of tocilizumab was concentration-dependent and is the sum of the linear and non-linear clearance. The linear clearance was estimated as a parameter in the population pharmacokinetic analysis and was 9.5 mL/h. The concentration-dependent non-linear clearance plays a major role at low tocilizumab concentrations. Once the non-linear clearance pathway is saturated, at higher tocilizumab concentrations, clearance is mainly determined by the linear clearance.
The t½ of tocilizumab was concentration-dependent. At steady-state following a dose of 8 mg/kg every 4 weeks, the effective t½ decreased with decreasing concentrations within a dosing interval from 18 days to 6 days.
Pharmacokinetic parameters of tocilizumab did not change with time. A more than dose-proportional increase in the AUC and Cmin was observed for doses of 4 and 8 mg/kg every 4 weeks. Cmax increased dose-proportionally. At steady-state, predicted AUC and Cmin were 3.2 and 30 fold higher at 8 mg/kg as compared to 4 mg/kg, respectively.
The pharmacokinetics of tocilizumab were determined using a population pharmacokinetic analysis on a database composed of 3552 RA patients treated with 162 mg subcutaneous every week, 162 mg subcutaneous every other week, and or 4 or 8 mg/kg intravenous every 4 weeks for 24 weeks.
The pharmacokinetic parameters of tocilizumab did not change with time. For the 162 mg every week dose, the predicted mean (±SD) steady-state AUC1week, Cmin and Cmax of tocilizumab were 7970 ± 3432 μg•h/mL, 43.0 ± 19.8 μg/mL, and 49.8 ± 21.0 μg/mL, respectively. The accumulation ratios for AUC, Cmin, and Cmax were 6.32, 6.30, and 5.27, respectively. Steady-state was reached after 12 weeks for AUC, Cmin, and Cmax.
For the 162 mg every other week dose, the predicted mean (±SD) steady-state AUC2week, Cmin, and Cmax of tocilizumab were 3430 ± 2660 μg•h/mL, 5.7 ± 6.8 μg/mL, and 13.2 ± 8.8 μg/mL, respectively.
The accumulation ratios for AUC, Cmin, and Cmax were 2.67, 6.02, and 2.12, respectively. Steady-state was reached after 12 weeks for AUC and Cmin, and after 10 weeks for Cmax.
Following subcutaneous dosing in RA patients, the time to peak serum tocilizumab concentrations tmax was 2.8 days. The bioavailability for the subcutaneous formulation was 79%.
For subcutaneous administration, the effective t1/2 is up to 13 days for 162 mg every week and 5 days for 162 mg every other week in patients with RA at steady-state.
The pharmacokinetics of tocilizumab was characterised using a population pharmacokinetic analysis of a database composed of 380 adult COVID-19 patients in Study WA42380 (COVACTA) and Study CA42481 (MARIPOSA) that treated with a single infusion of 8 mg/kg tocilizumab or two infusions separated by at least 8 hours. The following parameters (predicted mean ± SD) were estimated for a dose of 8 mg/kg tocilizumab: area under curve over 28 days (AUC0-28) = 18312 (5184) hour•μg/mL, concentration at Day 28 (Cday28) = 0.934 (1.93) μg/mL and maximum concentration (Cmax) = 154 (34.9) μg/mL. The AUC0-28, Cday28 and Cmax, following two doses of 8 mg/kg tocilizumab separated by 8 hours, were also estimated (predicted mean ± SD): 42240 (11520) hour•μg/mL and 8.94 (8.5) μg/mL, and 296 (64.7) μg/mL respectively.
In COVID-19 adult patients, the central volume of distribution was 4.52 L, the peripheral volume of distribution was 4.23 L, resulting in a volume of distribution of 8.75 L.
Following intravenous administration, tocilizumab undergoes a dual elimination from the circulation, one following a linear clearance and one following a concentration-dependent non-linear clearance. In COVID-19 adult patients, the linear clearance was 17.6 mL/h in patients with baseline ordinal scale category 3 (OS 3, patients requiring supplemental oxygen), 22.5 mL/h in patients with baseline OS 4 (patients requiring high-flow oxygen or non-invasive ventilation), 29 mL/h in patients with baseline OS 5 (patients requiring mechanical ventilation), and 35.4 mL/h in patients with baseline OS 6 (patients requiring extracorporeal membrane oxygenation (ECMO) or mechanical ventilation and additional organ support). The concentration-dependent non-linear clearance plays a major role at low tocilizumab concentrations. Once the non-linear clearance pathway is saturated, at higher tocilizumab concentrations, clearance is mainly determined by the linear clearance.
In COVID-19 patients, serum concentrations were below the limit of quantification after 35 days on average following one infusion of tocilizumab intravenous 8 mg/kg.
Pharmacokinetic parameters of tocilizumab did not change with time. A more than dose-proportional increase in the AUC and Cmin was observed for doses of 4 and 8 mg/kg every 4 weeks. Cmax increased dose-proportionally. At steady-state, predicted AUC and Cmin were 3.2 and 30 fold higher at 8 mg/kg as compared to 4 mg/kg, respectively.
The pharmacokinetics of tocilizumab in sJIA patients was characterised by a population pharmacokinetic analysis which included 140 patients who were treated with 8 mg/kg intravenous every 2 weeks (patients weighing ≥30 kg), 12 mg/kg intravenous every 2 weeks (patients weighing below 30 kg), 162 mg subcutaneous every week (patients weighing ≥30 kg), 162 mg subcutaneous every 10 days or every 2 weeks (patients weighing below 30 kg).
Limited data are available regarding exposures following subcutaneous administration of tocilizumab in sJIA patients below 2 years of age with a body weight less than 10 kg.
Patients with sJIA must have a minimum body weight of 10 kg when receiving tocilizumab subcutaneously.
Table 1. Predicted mean ± SD PK parameters at steady-state after subcutaneous dosing in sJIA:
| Tocilizumab PK Parameter | 162 mg QW ≥30 kg | 162 mg Q2W below 30 kg |
|---|---|---|
| Cmax (μg/mL) | 99.8 ± 46.2 | 134 ± 58.6 |
| Cmin (μg/mL) | 79.2 ± 35.6 | 65.9 ± 31.3 |
| Cmean (μg/mL) | 91.3 ± 40.4 | 101 ± 43.2 |
| Accumulation Cmax | 3.66 | 1.88 |
| Accumulation Cmin | 4.39 | 3.21 |
| Accumulation Cmean or AUCτ* | 4.28 | 2.27 |
* τ = 1 week or 2 weeks for the two SC regimens
After subcutaneous dosing, approximately 90% of the steady-state was reached by week 12 for both the 162 mg QW and Q2W regimens.
Table 2. Predicted mean ± SD PK parameters at steady-state after intravenous dosing in sJIA:
| Tocilizumab PK parameter | 8 mg/kg Q2W ≥30 kg | 12 mg/kg Q2W below 30 kg |
|---|---|---|
| Cmax (μg/mL) | 256 ± 60.8 | 274 ± 63.8 |
| Ctrough (μg/mL) | 69.7 ± 29.1 | 68.4 ± 30.0 |
| Cmean (μg/mL) | 119 ± 36.0 | 123 ± 36.0 |
| Accumulation Cmax | 1.42 | 1.37 |
| Accumulation Ctrough | 3.20 | 3.41 |
| Accumulation Cmean or AUCτ* | 2.01 | 1.95 |
* τ = 2 weeks for intravenous regimens
After intravenous dosing, approximately 90% of the steady-state was reached by week 8 for both the 12 mg/kg (body weight <30 kg) and 8 mg/kg Q2W (body weight ≥30 kg) regimens.
In sJIA patients, the central volume of distribution was 1.87 L and the peripheral volume of distribution was 2.14 L resulting in a volume of distribution at a steady-state of 4.01 L. The linear clearance estimated as a parameter in the population pharmacokinetic analysis, was 5.7 mL/h.
The half-life of tocilizumab in sJIA patients is up to 16 days for the two body weight categories (8 mg/kg for body weight ≥30 kg or 12 mg/kg for body weight <30 kg) at week 12.
Following subcutaneous dosing in sJIA patients, the absorption half-life was around 2 days, and the bioavailability for the subcutaneous formulation in sJIA patients was 95%.
In paediatric patients with sJIA, the central volume of distribution was 1.87 L, the peripheral volume of distribution was 2.14 L resulting in a volume of distribution at steady-state of 4.01 L.
The total clearance of tocilizumab was concentration-dependent and is the sum of the linear clearance and the nonlinear clearance. The linear clearance was estimated as a parameter in the population pharmacokinetic analysis and was 5.7 mL/h in paediatric patients with systemic juvenile idiopathic arthritis. Following subcutaneous administration, the effective t1/2 of tocilizumab in sJIA patients is up to 14 days for both the 162 mg QW and Q2W regimens during a dosing interval at steady-state.
The pharmacokinetics of tocilizumab in pJIA patients was characterised by a population pharmacokinetic analysis which included 237 patients who were treated with 8 mg/kg intravenous every 4 weeks (patients weighing ≥30 kg), 10 mg/kg intravenous every 4 weeks (patients weighing below 30 kg), 162 mg subcutaneous every 2 weeks (patients weighing ≥30 kg), or 162 mg subcutaneous every 3 weeks (patients weighing below 30 kg).
Table 3. Predicted mean ± SD PK parameters at steady-state after subcutaneous dosing in pJIA:
| Tocilizumab PK Parameter | 162 mg Q2W ≥30 kg | 162 mg Q3W below 30 kg |
|---|---|---|
| Cmax (μg/mL) | 29.4 ± 13.5 | 75.5 ± 24.1 |
| Cmin (μg/mL) | 11.8 ± 7.08 | 18.4 ± 12.9 |
| Cavg (μg/mL) | 21.7 ± 10.4 | 45.5 ± 19.8 |
| Accumulation Cmax | 1.72 | 1.32 |
| Accumulation Cmin | 3.58 | 2.08 |
| Accumulation Cmean or AUCτ* | 2.04 | 1.46 |
* τ = 2 week or 3 week for the two subcutaneous regimens
After intravenous dosing, approximately 90% of the steady-state was reached by week 12 for the 10 mg/kg (body weight <30 kg), and by week 16 for the 8 mg/kg (body weight ≥30 kg) dose. After subcutaneous dosing, approximately 90% of the steady-state was reached by week 12 for both the 162 mg subcutaneous Q2W and Q3W regimens.
Table 4. Predicted mean ± SD PK parameters at steady-state after intravenous dosing in pJIA:
| Tocilizumab PK parameter | 8 mg/kg Q4W ≥30 kg | 10 mg/kg Q4W below 30 kg |
|---|---|---|
| Cmax (μg/mL) | 183 ± 42.3 | 168 ± 24.8 |
| Ctrough (μg/mL) | 6.55 ± 7.93 | 1.47 ± 2.44 |
| Cmean (μg/mL) | 42.2 ± 13.4 | 31.6 ± 7.84 |
| Accumulation Cmax | 1.04 | 1.01 |
| Accumulation Ctrough | 2.22 | 1.43 |
| Accumulation Cmean or AUCτ* | 1.16 | 1.05 |
* τ = 4 weeks for intravenous regimens
The half-life of tocilizumab in pJIA patients is up to 16 days for the two body weight categories (8 mg/kg for body weight ≥30 kg or 10 mg/kg for body weight <30 kg) during a dosing interval at steady-state.
Following subcutaneous dosing in pJIA patients, the absorption half-life was around 2 days, and the bioavailability for the subcutaneous formulation in pJIA patients was 96%.
In paediatric patients with pJIA, the central volume of distribution was 1.97 L, the peripheral volume of distribution was 2.03 L, resulting in a volume of distribution at steady-state of 4.0 L.
Population pharmacokinetic analysis for pJIA patients showed body size related impact on linear clearance so that body-weight based dosing should be taken into consideration (see Table 5).
After subcutaneous administration, the effective t½ of tocilizumab in pJIA patients is up to 10 days for patients <30 kg (162 mg subcutaneous Q3W) and up to 7 days for patients ≥30 kg (162 mg subcutaneous Q2W) during a dosing interval at steady-state. Following intravenous administration, tocilizumab undergoes biphasic elimination from the circulation. The total clearance of tocilizumab was concentration-dependent and is the sum of the linear and non-linear clearance. The linear clearance was estimated as a parameter in the population pharmacokinetic analysis and was 6.25 mL/h. The concentration-dependent non-linear clearance plays a major role at low tocilizumab concentrations. Once the non-linear clearance pathway is saturated, at higher tocilizumab concentrations, clearance is mainly determined by the linear clearance.
The PK of tocilizumab in GCA patients were determined using a population PK model from an analysis dataset composed of 149 GCA patients treated with 162 mg subcutaneous every week or 162 mg subcutaneous every other week. The developed model had the same structure as the population PK model developed earlier based on data from RA patients (see Table 5).
Table 5. Predicted mean ± SD PK parameters at steady-state after subcutaneous dosing in GCA:
| Subcutaneous | ||
|---|---|---|
| Tocilizumab PK parameter | 162 mg every other weekly | 162 mg weekly |
| Cmax (μg/mL) | 19.3 ± 12.8 | 73 ± 30.4 |
| Ctrough (μg/mL) | 11.1 ± 10.3 | 68.1 ± 29.5 |
| Cmean (μg/mL) | 16.2 ± 11.8 | 71.3 ± 30.1 |
| Accumulation Cmax | 2.18 | 8.88 |
| Accumulation Ctrough | 5.61 | 9.59 |
| Accumulation Cmean or AUCτ* | 2.81 | 10.91 |
* τ = 2 week or 1 week for the two subcutaneous regimens
The steady-state profile following the tocilizumab weekly dose was almost flat, with very little fluctuations between trough and peak values, while there were substantial fluctuations for the every other week dose. Approximately 90% of the steady-state (AUCτ) was reached by week 14 in the every other week group and by week 17 in the weekly dose groups.
Based on the current characterization of PK, tocilizumab trough concentration at steady-state are 50% higher in this population relative to average concentrations in a large dataset from the RA population. These differences occur due to unknown reasons. PK differences are not accompanied by marked differences in PD parameters and so the clinical relevance is unknown.
In GCA patients, higher exposure was observed in patients with lower body weight. For the 162 mg every week dosing regimen, the steady-state Cavg was 51% higher in patients with body weight less than 60 kg compared to patients weighing between 60 to 100 kg. For the 162 mg every other week regimen, the steady-state Cavg was 129% higher in patients with body weight less than 60 kg compared to patients weighing between 60 to 100 kg. There is limited data for patients above 100 kg (n=7).
Following subcutaneous dosing in GCA patients, the absorption t½ was around 4 days. The bioavailability for the subcutaneous formulation was 0.8. The median values of Tmax were 3 days after the tocilizumab weekly dose and 4.5 days after the tocilizumab every other week dose.
In GCA patients, the central volume of distribution was 4.09 L, the peripheral volume of distribution was 3.37 L, resulting in a volume of distribution at steady-state of 7.46 L.
The total clearance of tocilizumab was concentration-dependent and is the sum of the linear clearance and the nonlinear clearance. The linear clearance was estimated as a parameter in the population pharmacokinetic analysis and was 6.7 mL/h in GCA patients,
In GCA patients, at steady-state, the effective t½ of tocilizumab varied between 18.3 and 18.9 days for 162 mg weekly regimen, and between 4.2 and 7.9 days for 162 mg every other weekly regimen. At high serum concentrations, when total clearance of tocilizumab is dominated by linear clearance, an effective t½ of approximately 32 days was derived from the population parameter estimates.
No formal study of the effect of renal impairment on the pharmacokinetics of tocilizumab has been conducted. Most of the patients in the RA and GCA studies population pharmacokinetic analysis had normal renal function or mild renal impairment. Mild renal impairment (estimated creatinine clearance based on Cockcroft-Gault formula) did not impact the pharmacokinetics of tocilizumab.
Approximately one-third of the patients in the GCA study had moderate renal impairment at baseline (estimated creatinine clearance of 30-59 mL/min). No impact on tocilizumab exposure was noted in these patients.
No dose adjustment is required in patients with mild or moderate renal impairment.
No formal study of the effect of hepatic impairment on the pharmacokinetics of tocilizumab has been conducted.
Population pharmacokinetic analyses in RA, COVID-19 and GCA patients, showed that age, gender and ethnic origin did not affect the pharmacokinetics of tocilizumab.
Results of the population PK analysis for COVID-19 patients confirmed that body weight and disease severity are both covariates which have an appreciable impact on the linear clearance of tocilizumab.
Results of the population PK analysis for sJIA and pJIA patients confirmed that body size is the only covariate which has an appreciable impact on the pharmacokinetics of tocilizumab including elimination and absorption so that body-weight based dosing should be taken into consideration (see Tables 1 and 3).
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and toxicity to reproduction and development.
Carcinogenicity studies were not performed because IgG1 monoclonal antibodies are not deemed to have intrinsic carcinogenic potential.
Available non-clinical data demonstrated the effect of IL-6 on malignant progression and apoptosis resistance to various cancer types. This data does not suggest a relevant risk for cancer initiation and progression under tocilizumab treatment. Additionally, proliferative lesions were not observed in a 6-month chronic toxicity study in cynomolgus monkeys or in IL-6 deficient mice.
Available non-clinical data do not suggest an effect on fertility under tocilizumab treatment. Effects on endocrine active and reproductive system organs were not observed in a chronic cynomolgus monkey toxicity study and reproductive performance was not affected in IL-6 deficient mice. Tocilizumab administered to cynomolgus monkeys during early gestation, was observed to have no direct or indirect harmful effect on pregnancy or embryonal-foetal development. However, a slight increase in abortion/embryonal-foetal death was observed with high systemic exposure (>100 × human exposure) in the 50 mg/kg/day high-dose group compared to placebo and other low-dose groups. Although IL-6 does not seem to be a critical cytokine for foetal growth or the immunological control of the maternal/foetal interface, a relation of this finding to tocilizumab cannot be excluded.
Treatment with a murine analogue did not exert toxicity in juvenile mice. In particular, there was no impairment of skeletal growth, immune function and sexual maturation.
The non-clinical safety profile of tocilizumab in the cynomolgus monkey does not suggest a difference between intravenous and subcutaneous routes of administration.
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