Clinical pharmacology of tocilizumab for the treatment of patients with rheumatoid arthritis

Abstract

Tocilizumab is a humanized anti-IL-6 receptor (IL-6R) monoclonal antibody for the treatment of rheumatoid arthritis (RA). A dose of 8 mg/kg produces adequate blockade of IL-6 receptors throughout a dosing interval, as confirmed by sustained high levels of tocilizumab-bound soluble IL6-R complex and normalization of C-reactive protein levels. Studies have confirmed 8 mg/kg every 4 weeks as the optimal dose and 4 mg/kg as the starting dose for the treatment of RA, with favorable efficacy and acceptable safety profiles. After 8 mg/kg, steady-state peak and trough concentrations were 183 ± 86 and 9.7 ± 11 µg/ml, respectively. Tocilizumab serum exposures increased more than proportionally to the dose increase from 2–10 mg/kg. Total clearance is concentration dependent, with non-linear receptor-mediated clearance dominant at low concentrations (<25 µg/ml). Tocilizumab exposures are not affected by common concomitant medications in RA patients, but decreased IL-6 activity resulted in increased CYP3A4 activity and hence decreased exposures of CYP3A4 substrates.

Keywords::

• Actemra^®
• clinical pharmacology
• C-reactive protein
• exposure–response relationship
• interleukin-6 receptor
• interleukin-6
• pharmacokinetics
• rheumatoid arthritis
• tocilizumab

Author note

In cases of currently unpublished pharmacology data mentioned throughout this manuscript, all results are final and have been submitted to regulatory agencies as part of licensing approval.

Acknowledgements

The authors gratefully acknowledge Francisco Ramirez for statistical analysis of tocilizumab efficacy and safety data by exposure quartiles, and Olivier Harari and Denise Lepley for their assistance with the development of this article.

Financial & competing interests disclosure

This article was funded by Roche. Xiaoping Zhang and Richard Peck are employees of Roche. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.