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.

A randomized, double-blind, parallel-group, phase III study of shortening the dosing interval of subcutaneous tocilizumab monotherapy in patients with rheumatoid arthritis and an inadequate response to subcutaneous tocilizumab every other week: Results of the 12-week double-blind period

“…During the MUSASHI open-label period, patients with an inadequate response to TCZ-SC q2w could have their dosing interval shortened and receive TCZ-SC qw, which resulted in increased TCZ serum trough levels and improved efficacy with a comparable safety profile [12]. In pharmacokinetic and pharmacodynamic analyses of TCZ-SC in patients from the SUMMACTA and BREVACTA trials, body weight was an important covariate affecting clearance and volume of distribution; the observed mean TCZ trough levels for patients !100 kg were lower with TCZ-SC q2w compared with TCZ-SC qw [13]. Together, these results suggest that patients with an inadequate response to TCZ-SC q2w and low TCZ serum trough levels may benefit from a shortened dosing interval [11][12][13].…”

Safety and effectiveness of subcutaneous tocilizumab in patients with rheumatoid arthritis in a real-world clinical setting

“…TCZ-SC was given at a fixed dose, and patients with a higher BMI may fail to maintain serum trough concentrations of TCZ required for a response. Previous studies showed that following a switch from TCZ-IV every 4 weeks to TCZ-SC every 2 weeks, patients with higher body weight had reduced TCZ serum trough concentrations and reduced efficacy [18,26].…”

A Review of Recent Advances Using Tocilizumab in the Treatment of Rheumatic Diseases

“…In addition, population PK analyses of 75 patients with sJIA and 188 patients with pJIA have been conducted to determine the PK of TCZ-IV in these patients (F. Hoffmann-La Roche Ltd., data on file). We have summarized the PK profiles in Table 1 [37,72,73]. PK exposure parameters for TCZ were found to be similar between healthy individuals and patients with RA, indicating that even the presence of active disease does not impact the PK profile of TCZ [74].…”

“…However, patients treated with TCZ should be monitored for malignancies to provide data that can be used for to assess risk over the longer term. The data for the pharmacokinetics (PK) of TCZ-IV and TCZ-SC are based on population PK analyses of 1793 and 1759 patients with RA, respectively [72][73][74]. In addition, population PK analyses of 75 patients with sJIA and 188 patients with pJIA have been conducted to determine the PK of TCZ-IV in these patients (F. Hoffmann-La Roche Ltd., data on file).…”