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

Authors
  • Abdallah, Hisham1
  • Hsu, Joy C1
  • Lu, Peng1
  • Fettner, Scott1
  • Zhang, Xiaoping1
  • Douglass, Wendy2
  • Bao, Min3
  • Rowell, Lucy2
  • Burmester, Gerd R4
  • Kivitz, Alan5
  • 1 Roche Innovation Center, New York, NY, USA.
  • 2 Roche, Welwyn Garden City, London, UK.
  • 3 Genentech, Inc, South San Francisco, CA, USA.
  • 4 Charité-Universitätsmedizin Berlin, Free University and Humboldt University of Berlin, Berlin, Germany. , (Germany)
  • 5 Altoona Center for Clinical Research, Duncansville, PA, USA.
Type
Published Article
Journal
Journal of clinical pharmacology
Publication Date
Apr 01, 2017
Volume
57
Issue
4
Pages
459–468
Identifiers
DOI: 10.1002/jcph.826
PMID: 27599663
Source
Medline
Keywords
License
Unknown

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.

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