A TOCILIZUMAB DOSING STRATEGY IN RHEUMATOID ARTHRITIS PATIENTS WITH STABLE DISEASE AIMING TO PREVENT OVERTREATMENT AND UNNECESSARY COSTS

Background: Tocilizumab (TCZ) is a humanized interleukin 6 (IL-6) antibody that competitively inhibits IL-6 signalling by binding both membrane-bound and soluble IL-6 receptors. The EULAR recommends the use of TCZ, as a biological disease-modifying antirheumatic drug (DMARD), as second line therapy in rheumatoid arthritis (RA) when conventional DMARDs have failed achieving treatment target. The labelled dosing regimen for TCZ in RA is 8mg/kg (maximum 800mg) every 4 weeks. A TCZ predose serum concentration (TCZpsc) >1mg/L normalizes C-reactive protein, while clinical trials found mean TCZpsc of 19.9 ±17.0 mg/L in patients receiving the standard regimen. On the basis of these data, it can be hypothesized that cost-effectiveness of therapy can be improved. Objectives: In this study we evaluated TCZpsc in stable RA-patients to determine whether the TCZ 8mg/kg dose could be lowered while meeting the minimal required concentration for effective blockage of the IL-6 inflammatory cascade. Methods: Adult RA patients with stable disease (i.e. at least 3 months without treatment change) treated with intravenous TCZ were investigated in a prospective cohort study. TCZpsc before two different TCZ infusions over time was assessed. A validated ELISA was used to measure TCZpscs, immunogenicity was measured by quantifying human antibodies using antigen-binding tests (radioimmunoassay). A population pharmacokinetic (PK) model was constructed using maximum a posteriori Bayesian estimation applied on the available PK data in the literature combined with the collected data on dosing and predose concentrations in the study patients. Body surface area, creatinine clearance and gender were included as covariates in the model. A patient individual dose tapering strategy was predicted based on the derived model. The target TCZpsc was set on 8-10mg/L taking the measurement error of 15%, the use of the entire content of the vials and intra-individual variation into consideration. Results: A total of 44 patients were included [median (IQR) age: 63 (58-72), 75% female, mean (SD) DAS28-ESR: 1.5 (0.8)]. Half of the patients received TCZ in combination with a conventional DMARD, 32% used methotrexate (MTX). Patients received 7.7 ±0.8mg/kg (range 5.7-9.7) TCZ. Mean TCZpsc was 27.6 ±12.6mg/L. The intra-individual variance of TCZpsc was low; mean difference in individual TCZpscs was 0.56 (5.2)mg/L. Higher dosages (in mg/kg) were significantly associated with higher TCZpsc (regression coefficient 7.32 95%CI 2.73;11.9), suggesting overtreatment. No drug-neutralizing auto-antibodies were measured. Co-treatment with MTX did not influence the median TCZpsc (21.0mg/L versus 26.5mg/L without MTX, p=0.84). According to the measured TCZpsc, TCZ dosage could be lowered in 36 patients (92%). In a 28-days regimen, target-TCZpsc would be reached with a 0.4-4.6mg/kg dose-reduction ( Figure 1 ). Extending the interval between two administrations would lead to low TCZpsc (<1mg/L). Figure 1. Intended dose reduction related to the measured tocilizumab predose serum concentration Considering the aimed average dose-reduction of 2.1 mg/kg per administration, efficacy would be expected to maintain (TCZpsc >1 mg/L) while reducing yearly costs with ±€3.900,- per patient. On average patients were started on TCZ treatment 63 months (SD26) earlier. As maximum efficacy of TCZ treatment can be achieved after 3 months, TCZpsc-guided dose reduction 3 months after start could have resulted in a total drug cost reduction of ±€750.000,- in our study population (±€19.500,- per patient). Conclusion: Measured TCZpsc under standard TCZ therapy was much higher than the minimal required concentration. These results suggest that the labelled TCZ dose leads to overtreatment and unnecessary costs in patients with stable RA. The TCZpsc seems supportive as an instrument for dose reduction strategies. Future prospective studies should assess its use in TCZ dose adjustment and confirm whether treatment efficacy is maintained. Disclosure of Interests: None declared Citation: Ann Rheum Dis, volume 80, supplement 1, year 2021, page 540Session: Rheumatoid arthritis - biological DMARDs (POSTERS only)