Pharmacokinetic and Pharmacodynamic Analysis of Subcutaneous Tocilizumab in Patients With Rheumatoid Arthritis From 2 Randomized, Controlled Trials: SUMMACTA and BREVACTA
Open Access
- 17 November 2016
- journal article
- research article
- Published by Wiley in The Journal of Clinical Pharmacology
- Vol. 57 (4), 459-468
- https://doi.org/10.1002/jcph.826
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
Funding Information
- F Hoffmann-La Roche Ltd
This publication has 18 references indexed in Scilit:
- EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 updateAnnals Of The Rheumatic Diseases, 2013
- Drug adherence to biologic DMARDS with a special emphasis on the benefits of subcutaneous abataceptPatient Preference and Adherence, 2012
- 2012 Update of the 2008 American College of Rheumatology recommendations for the use of disease‐modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritisArthritis Care & Research, 2012
- Biologics-Based Therapy for the Treatment of Rheumatoid ArthritisClinical Pharmacology & Therapeutics, 2011
- Patient preferences and satisfaction in the treatment of rheumatoid arthritis with biologic therapyPatient Preference and Adherence, 2009
- Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti–IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman diseaseBlood, 2008
- The comparative efficacy and safety of biologics for the treatment of rheumatoid arthritis: a systematic review and metaanalysis.2006
- Patient preferences in choosing anti-TNF therapies-R1Rheumatology, 2006
- Tocilizumab inhibits signal transduction mediated by both mIL-6R and sIL-6R, but not by the receptors of other members of IL-6 cytokine familyInternational Immunopharmacology, 2005
- Does route of administration affect the outcome of TNF antagonist therapy?Arthritis Research & Therapy, 2004