Comparison of rituximab induction and maintenance regimens in anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis: PK/PD modelling of ANCA and gammaglobulin levels in real-world patients

BACKGROUND: We aimed to provide pharmacokinetic-pharmacodynamic (PK/PD) rationale for selecting the optimal induction and maintenance dosing regimens in ANCA-associated vasculitis (AAV) using a population modelling approach based on PK, ANCA, and gammaglobulins data from a real-world cohort. METHODS: weekly for 4 weeks and 1000 mg on day 0 and 14) and maintenance regimens (500 mg every 6 months [Q6M], 500 mg Q6M starting at month 4, 1000 mg Q4M, 500 mg Q4M) were performed in 1000 virtual patients. Dosing regimens were compared using a clinical utility score that equally weighted the percentage of patients in serological remission and at risk of hypogammaglobulinaemia (<6 g/L). FINDINGS: The PK/PD model satisfactorily described the relationship between rituximab, gammaglobulins and ANCA concentrations over time. Both induction regimens resulted in a similar number of patients achieving serological remission and hypogammaglobulinaemia at 6 months. In the maintenance phase, increasing the dose (to 1000 mg) or the frequency of administration (Q4M versus Q6M) was associated with a higher number of patients with serological remission at month 24, but also with a higher risk of hypogammaglobulinaemia. In the maintenance phase, 500 mg Q6M (start at month 4 or 6), had a significantly higher utility score than 1000 mg Q4M. INTERPRETATION: This PK/PD study can inform clinical decisions regarding the choice between different rituximab induction and maintenance regimens in patients with AAV in daily practice.