Rheumatoid Arthritis -Treatment 52 by IL-6 at concentrations of > 0.32 ng/mL, and no inhibition of cell growth by TCZ was observed in the presence of 1 µg/mL IL-6 (Australian Government, 2011). In vivo, serum levels of IL-6 and sIL-6R markedly increased after TCZ treatment in patients with RA. While free TCZ concentration remains 1 µg/mL or more, serum C-reactive protein (CRP) is normalized, indicating that sIL-6R is saturated with TCZ and IL-6 signaling is completely inhibited .

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... properties PK data were based on a population PK analysis of 1793 patients with RA who received a 1 hour infusion of TCZ 8mg/kg every 4 weeks for 24 weeks (Frey et al., 2010). The t 1/2 of TCZ was concentration-dependent. The effective t 1/2 decreased with decreasing concentrations of TCZ within a dosing interval from 14 days to 8 days. After administration of TCZ, the predicted steady-state the mean area under the concentration-time curve (AUC), maximum concentration (C max ), the steady-state volume of distribution, and the trough concentration (C min ) values were 35.0 mg·h/mL, 183 µg/mL, 6.4 L, and 9.7 µg/mL, respectively. The Cmin value is 91 fold higher that the Kd of TCZ for the binding at the sIL-6R (Kd is 0.71 nM = 0.10 µg/ml). Therefore, IL-6R was completely occupied even at the end of each 8 mg/kg dosing interval in most of the patients. Age, gender and ethnicity did not affect the PK of TCZ. TCZ is not excreted via the renal or biliary route. Instead, TCZ is predominantly eliminated via catabolism including degradation in plasma and distribution to tissues. TCZ undergoes biphasic elimination from the circulation. Total clearance is concentration dependent and includes linear at higher TCZ concentrations and non-linear clearance at low TCZ concentration. No formal studies on the effect of renal or hepatic impairment on the PK of TCZ have been conducted. Mild renal impairment (creatinine clearance based on Cockcroft-Gault < 80 ml/min and ≥ 50 ml/min) did not affect the PK of TCZ. Nor is the clearance of TCZ affected by concomitant use of methotrexate (MTX), nonsteroidal anti-inflammatory drugs (NSAIDs), or corticosteroids. TCZ may normalize the expression of hepatic cytochrome P450 (CYP) isozymes which are suppressed by IL-6 (Oldfield et al., 2009). Therefore, administration or discontinuation of TCZ may affect the serum concentrations of drugs metabolized via CYP3A4, CYP1A2, CYP2C9 or CYP2C19 (e.g., omeprazole, dextromethorphan, atorvastatin, simvastatin, calcium channel blockers, cyclosporine, and warfarin). Therapeutic efficacy Clinical studies In a 12-week, multicenter, randomized, double-blind, placebo-controlled phase I/II study, 164 Japanese patients with refractory RA were randomly administered either placebo, or 4 mg/kg or 8 mg/kg TCZ (Nishimoto et al., 2004). A dose-dependent reduction in the American College of Rheumatology (ACR) 20 response was observed. At 3 months, 78% of patients in the 8 mg/kg group, 57% in the 4 mg/kg group, and 11% in the placebo group achieved an ACR20 response. This study was extended to evaluate the long-term efficacy and safety of TCZ 8 mg/kg monotherapy for five years and designated STREAM (long-term Safety and efficacy of Tocilizumab, an anti-interleukin-6 REceptor monoclonal Antibody, in Monotherapy, in patients with rheumatoid arthritis) (Nishimoto et al., 2009a) . A total 143 patients were enrolled, and 94 patients completed 5 years. At 5 years, 84.0%, 69.1%, and