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

Abstract

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: A total of 121 patients with 296 plasma rituximab concentrations (99 and 197 in the induction and maintenance phases, respectively), 439 ANCA levels and 559 gammaglobulin levels were included in the analysis. Simulations of induction (375 mg/m² 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.

Funding: This study received no funding.

Keywords: Anti-neutrophil cytoplasmic antibodies; Anti-neutrophil cytoplasmic antibodies-associated vasculitis; Gammaglobulins; PK/PD; Population pharmacokinetics; Rituximab.