Subcutaneous versus intravenous ultra-low dose rituximab in rheumatoid arthritis: a randomised controlled PK-PD non-inferiority trial

OBJECTIVES: Ultra-low dose rituximab is an effective treatment in rheumatoid arthritis (RA). Subcutaneous (SC) administration may further facilitate rituximab treatment, reduce infection risk, and reduce costs. This study aimed to assess non-inferiority of SC versus intravenous (IV) rituximab regarding pharmacokinetic and -dynamic (PKPD) outcomes. METHODS: In this randomised, open-label, non-inferiority study, RA patients with stable low disease activity on ultra-low dose rituximab (500 mg or 200 mg every 6 months) were 1:1 randomised to receive rituximab 336 mg SC or 200 mg IV, stratified by previous rituximab dose. Primary outcome was non-inferiority of SC to IV rituximab, based on the estimated rituximab serum concentration area under the curve during the first 6 months (AUC0-6 months), with a non-inferiority margin of 0.8. AUCs were estimated using PK modelling. Secondary outcomes included change in DAS28-CRP compared to a NI-margin of 0.6. RESULTS: Thirty-five patients were randomised (17 IV, 18 SC). The geometric mean ratio for AUC0-6m was 0.99 (90%-CI 0.82 to 1.20), with minimal bias (mean predication error: IV 13.1 (1.86%); SC -3.40 (-0.47%)) but moderate random prediction error (root mean square error: IV 140 (19.8%); SC 142 (19.5%)) for the AUC estimates. Mean change in DAS28-CRP was non-inferior for SC rituximab (-0.39, 95%-CI -0.77 to -0.004). CONCLUSION: Our data suggest non-inferior pharmacokinetics for SC rituximab; however, this cannot be definitively concluded due to uncertainty of the AUC estimates. Nevertheless, based on PK/PD parameters, ultra-low dose SC rituximab could be an alternative for ultra-low dose IV rituximab.