Pharmacokinetic and Pharmacodynamic Analysis of Subcutaneous Tocilizumab in Patients With Rheumatoid Arthritis From 2 Randomized, Controlled Trials: SUMMACTA and BREVACTA.
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.
Roche Innovation Center, New York, NY, USA.
Hisham
H
Abdallah
Roche Innovation Center, New York, NY, USA.
Joy C
JC
Hsu
Roche Innovation Center, New York, NY, USA.
Peng
P
Lu
Roche Innovation Center, New York, NY, USA.
Scott
S
Fettner
Roche Innovation Center, New York, NY, USA.
Xiaoping
X
Zhang
Roche, Welwyn Garden City, London, UK.
Wendy
W
Douglass
Genentech, Inc, South San Francisco, CA, USA.
Min
M
Bao
Roche, Welwyn Garden City, London, UK.
Lucy
L
Rowell
Charité-Universitätsmedizin Berlin, Free University and Humboldt University of Berlin, Berlin, Germany.
Gerd R
GR
Burmester
Altoona Center for Clinical Research, Duncansville, PA, USA.
Alan
A
Kivitz
D061605:Administration, Intravenous; D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000097:blood* / Q000493:pharmacokinetics; D018501:Antirheumatic Agents / Q000008:administration & dosage* / Q000097:blood* / Q000493:pharmacokinetics; D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged
D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; C502936:tocilizumab
pharmacokinetics; rheumatoid arthritis; subcutaneous; tocilizumab