Tocilizumab is a humanized monoclonal antibody targeting the IL-6 receptor (IL-6R). It has
proven to be effective in reducing inflammation and symptoms in rheumatoid arthritis (RA).
The registered standard dose of tocilizumab subcutaneously (sc) is 162 mg weekly for every
patient. All patients diagnosed with RA and treated with tocilizumab sc receive the same
dose, so treatment with expensive biologicals is currently based on a 'one size fits all'
approach. Because of the large inter-individual variability in the pharmacokinetics of
tocilizumab this standard dose results in a wide range of serum concentrations. In the search
to optimize the dose for individual patients it was demonstrated that serum levels of 1 mg/L
of tocilizumab are adequate to block the IL-6 receptor systemically, as indicated by a
reduction in CRP levels in patients with these low trough concentrations. Therefore, a
substantial proportion of patients is likely to be overexposed to tocilizumab. This
overtreatment is a waste of health care resources and might be associated with an increased
risk of adverse events, mainly infections.
We believe that overexposure can be reduced effectively by making use of the drug
concentrations found in the serum of individual patients. Our hypothesis is therefore that
reducing the dose in the setting of therapeutic drug monitoring (TDM) does not affect
clinical disease activity and safety, while it will reduce costs.
Based on previous studies we believe that a concentration around 5 mg/L is sufficient to
reach the maximal treatment effect. Therefore tapering strategy was developed aiming for
serum concentrations around 5 mg/L. Monte Carlo modelling was performed to determine the
cut-off concentration for interval prolongation to be used in this study. Simulations were
performed and it was found that patients with trough concentrations above 15 mg/L can safely
prolong their dosing interval, as this will result in levels around 5 mg/L in the majority of
patients.
This study is a 52 weeks randomised, multicenter, non-inferiority trial in rheumatoid
arthritis patients treated with subcutaneous tocilizumab 162 mg weekly for at least the
previous 6 months. After informed consent is obtained during the baseline visit, blood will
be drawn to measure drug trough concentrations. Patients with a tocilizumab concentration
above 15 mg/L will be randomly assigned to dose reduction by increasing their dosing-interval
from once every week to once every two weeks, or to continuation of their tocilizumab dose
(standard dose). After randomization, patients are followed for a period of 52 weeks. Data
regarding disease status and functioning will be collected during the baseline visit, and 12,
28, 40, and 52 weeks thereafter. Blood will also be drawn from the patients during these
visits. All patients with concentrations below 15 mg/L during the first study visit will not
be randomized and all continue standard treatment. Only one follow-up visit, after 52 weeks,
will be performed in this group of patients.
Patients can also choose to participate in a sub-study where the finger prick developed by
Sanquin (Amsterdam) will be validated to measure tocilizumab drug levels. This part of the
study will comprise performing three finger pricks. These finger pricks will be performed
during the visit at week 12 with the help of a nurse, and at home during the two weeks after
this visit.