Therapeutic Drug Monitoring of Tocilizumab in Rheumatoid Arthritis

INTRODUCTION AND RATIONALE Rheumatoid arthritis (RA) is a chronic inflammatory disease with a symmetric polyarthritis. One of the cytokines playing a role in RA is interleukin-6 (IL-6)(1;2). Tocilizumab is a humanized monoclonal antibody targeting IL-6 receptor (IL-6R) and is proved to be effective in reducing inflammation and symptoms in RA. Tocilizumab intravenously (IV) is approved by the European Medical agency (EMA) in a standard dose of 8 mg/kg every 4 weeks for RA patients. The FDA approved a standard dose of 4 mg/kg every 4 weeks, with a possibility to increase the dose to 8 mg/kg. This raises the question whether a proportion of patients treated with 8 mg/kg are overexposed.

Previously, it has been showed that 8 mg/kg results in a wide range of serum tocilizumab concentrations, although serum concentrations above 1 mg/L are reported to be sufficient to inhibit IL-6 signaling and to normalize CRP levels (CRP ≤ 10 mg/L), suggesting a systemic IL-6R blockade (3;4). In a previous study, the median tocilizumab concentration was 10.6 mg/L after 24 weeks of treatment, suggesting that a substantial proportion of patients is likely to be overexposed to tocilizumab (4). A recent study showed that overexposure, defined by high serum drug concentration, can be reduced in adalimumab-treated RA patients by prolonging the dose-interval (5). The wide variation in tocilizumab concentrations and sufficient target blockade at a fixed serum trough concentration suggests that a similar approach to reduce overexposure is possible in tocilizumab treatment too. Moreover, Levi and colleagues showed improvements in the disease activity score using 28 joints (DAS28) were associated with a C50 (concentration at which the 50% of the effect is achieved) between 2-5 µg/ml. (8) We, therefore, expect that patients can reduce the dose aiming at a concentration of 5 mg/L without reducing efficacy. Around 70% of the patients had a tocilizumab concentration above 5 mg/L in a previous study and can potentially reduce the dose (3).

Reducing overexposure is necessary in light of high drug costs and, possibly, the risk of adverse events. Therefore, our aim is to study whether overexposure can be reduced without affecting disease activity in tocilizumab-treated RA patients. We have developed an algorithm to reduce the dose in order to achieve a tocilizumab concentration of 5 mg/L in each patient.

OBJECTIVES Primary objective: To evaluate the feasibility of reducing the dose of tocilizumab according to serum trough levels at baseline, after 20 weeks follow-up.

Secondary objective: To evaluate the dose-reduction algorithm in tocilizumab-treated RA patients with tocilizumab concentrations above 5 mg/L after 20 weeks of follow-up.