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 (2.1)].
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 |
