Background Limited data is currently available regarding the pharmacokinetics (PK) and –dynamics (PD) of tocilizumab (TCZ) in daily clinical practice.
Objectives To assess the relationship between TCZ levels and clinical response in rheumatoid arthritis (RA) patients.
Methods Observational cohort study of 46 consecutive RA patients treated with TCZ 8 mg/kg intravenously once every 4 weeks in the Netherlands (n=25) and Spain (n=21), monitored during 48 weeks. Samples and clinical data were collected at least at baseline, week (w) 24 and 48. TCZ trough levels and titres of anti-drug antibodies (ADA) against TCZ were determined using an ELISA and an Antigen Binding Test (ABT), respectively. Samples which were not trough level were excluded. Disease activity was assessed using the Disease Activity Score of 28 joints (DAS28) and response was defined as a DAS28 remission (DAS28 score <2.6). Values are reported in mean ± SD or median (IQR).
Results At baseline patients had a DAS28 score of 5.5±1.4 and 8 patients were biological naive. Duration of follow-up varied between 12 to 48 weeks and 15 patients discontinued TCZ treatment before w48. At w24, 40% of the patients were in remission and at w48 44%. TCZ levels varied widely among patients, at w24 the median TCZ level (mg/L) was 9.6 (3.6-16.7). Figure 1 shows that patients with very low TCZ levels at w24, despite a dosage of 8 mg/kg per 4 weeks, had not improved (ΔDAS28) compared to baseline. Moreover, some patients had high TCZ levels without additional clinical benefit. No ADA against TCZ were detected. Non-parametric testing (not corrected for confounders) showed that TCZ levels at w24 (n=37) and w48 (n=26) were significantly higher in responders compared to non-responders, respectively, 20 (6.3-31.2) vs 6.9 (0.2-11.6) (p=0.004) and 15.5 (7.9-32.2) vs 6.8 (2.9-12.2) (p=0.025).
Conclusions Although TCZ trough levels vary greatly, immunogenicity does not seem to be an important factor in the PK/PD of TCZ. However, it might be possible, that ADA were not detected due to drug interference. Another explanation for the variation of TCZ trough levels could be target-binding. Furthermore, this study shows that TCZ trough levels are associated with clinical outcome in RA and that some patients are currently over- or undertreated with TCZ 8 mg/kg per 4 weeks. Therefore, assessing TCZ levels may help to optimize treatment in patient treated with TCZ.
Disclosure of Interest E. Kneepkens: None declared, I. Van Den Oever: None declared, C. Plasencia Grant/research support: Pfizer, D. Salcedo Pascual Grant/research support: Pfizer, Speakers bureau: Pfizer, M. Lopez-Casla: None declared, D. Van Der Kleij: None declared, M. Nurmohamed Consultant for: AbbVie, Roche, Pfizer, MSD, UCB, SOBI and BMS, Speakers bureau: AbbVie, Roche, Pfizer, T. Rispens Speakers bureau: AbbVie, A. Balsa Grant/research support: Pfizer, Speakers bureau: Pfizer, Roche, AbbVie, G. Wolbink Grant/research support: Pfizer, Speakers bureau: Pfizer, Amgen