Pharmacokinetic and Pharmacodynamic Analysis of Subcutaneous Tocilizumab in Patients With Rheumatoid Arthritis From 2 Randomized, Controlled Trials: SUMMACTA and BREVACTA

Abstract

Tocilizumab is a humanized anti-interleukin-6 receptor antibody for treating rheumatoid arthritis. Pharmacokinetic/pharmacodynamic analysis was performed on the 24-week double-blind parts of 2 randomized, controlled trials: SUMMACTA and BREVACTA. SUMMACTA compared subcutaneous tocilizumab 162 mg every week to intravenous tocilizumab 8 mg/kg every 4 weeks, whereas BREVACTA evaluated 162 mg subcutaneous tocilizumab every 2 weeks versus placebo. In addition to noncompartmental analysis, a 2-compartment population pharmacokinetic model, with first-order absorption (for subcutaneous) and linear and Michaelis-Menten elimination was used. Mean observed steady-state predose tocilizumab concentrations in week 24 were 40 and 7.4 μg/mL for subcutaneous every-week and every-2-week dosing, respectively, and 18 μg/mL for intravenous dosing. In the population PK model, body weight was an important covariate affecting clearance and volume of distribution. Mean ± SD population-predicted predose concentration for patients ≥100 kg was 23.0 ± 13.5 μg/mL for subcutaneous tocilizumab every week and 1.0 ± 1.6 μg/mL for every 2 weeks. Efficacy was lowest with subcutaneous every-2-week dosing in patients > 100 kg, reflecting lower exposure. The subcutaneous every-2-week regimen is not recommended for these patients. Pharmacodynamic responses were comparable for the every-week subcutaneous and every-4-week intravenous regimens and less pronounced with the every-2-week subcutaneous regimen. No trend was observed for increased adverse events with increasing tocilizumab exposure. The results of this analysis are consistent with the noninferiority of efficacy of the every-week subcutaneous regimen to the every-4-week intravenous regimen and the superiority of the every-2-week subcutaneous regimen to placebo. These results support the label recommendations for subcutaneous dosing of tocilizumab in rheumatoid arthritis patients.

Keywords: pharmacokinetics; rheumatoid arthritis; subcutaneous; tocilizumab.

Figure 1

Mean observed predose tocilizumab concentrations for SC QW, SC Q2W, or IV Q4W dosing. Error bars show standard error. IV, intravenous; Q2W, every 2 weeks; Q4W, every 4 weeks; QW, weekly; SC, subcutaneous; TCZ, tocilizumab.

Figure 2

Simulated tocilizumab serum concentrations over time at steady state. Black line, tocilizumab 8 mg/kg IV Q4W; blue line, tocilizumab 162 mg SC QW; green line, tocilizumab 162 mg SC Q2W. IV, intravenous; Q2W, every 2 weeks; Q4W, every 4 weeks; QW, weekly; SC, subcutaneous; TCZ, tocilizumab.

Figure 3

Mean IL‐6 (A), sIL‐6R (B), CRP (C), and ESR (D) levels following treatment with SC or IV tocilizumab. Error bars show standard error. CRP, C‐reactive protein; ESR, erythrocyte sedimentation rate; IL‐6, interleukin 6; IV, intravenous; Q2W, every 2 weeks; Q4W, every 4 weeks; QW, weekly; SC, subcutaneous; sIL‐6R, soluble IL‐6 receptor; TCZ, tocilizumab.