Pharmacokinetics of rituximab and clinical outcomes in patients with anti-neutrophil cytoplasmic antibody associated vasculitis

Abstract

Objectives: To study the determinants of the pharmacokinetics (PK) of rituximab (RTX) in patients with ANCA-associated vasculitis (AAV) and its association with clinical outcomes.

Methods: This study included data from 89 patients from the RTX in AAV trial who received the full dose of RTX (four weekly infusions of 375 mg/m2). RTX was quantified at weeks 2, 4, 8, 16 and 24, and summarized by computing the trapezoidal area under the curve. We explored potential determinants of the PK-RTX, and analysed its association with clinical outcomes: achievement of remission at 6 months, duration of B-cell depletion and time to relapse in patients who achieved complete remission.

Results: RTX serum levels were significantly lower in males and in newly diagnosed patients, and negatively correlated with body surface area, baseline B-cell count and degree of disease activity. In multivariate analyses, the main determinants of PK-RTX were sex and new diagnosis. Patients reaching complete remission at month 6 had similar RTX levels compared with patients who did not reach complete remission. Patients with higher RTX levels generally experienced longer B-cell depletion than patients with lower levels, but RTX levels at the different time points and area under the curve were not associated with time to relapse.

Conclusion: Despite the body-surface-area-based dosing protocol, PK-RTX is highly variable among patients with AAV, its main determinants being sex and newly diagnosed disease. We did not observe any relevant association between PK-RTX and clinical outcomes. The monitoring of serum RTX levels does not seem clinically useful in AAV.

Fig. 1

Correlation between rituximab serum levels at different time points and duration of B cell depletion The duration of B-cell depletion was computed in each patient as the time between the date of the first rituximab infusion and the date of the first visit with B cells ≥10/µl. The correlation with serum levels of rituximab at the different visits was assessed by Spearman’s test.

Fig. 2

Association between rituximab serum levels and time to relapse and to B cell redetection Serum rituximab levels by ELISA at each visit were analysed as tertiles, the lowest tertile (tertile 1) considered as the reference for time to event comparison with tertiles 2 and 3 (respectively, medium and highest rituximab levels) using Cox proportional hazards models. Time to any flare and time to severe flare were analysed in patients who reached complete remission, and time to B cell redetection (defined as B cells ≥10/µl) was analysed considering flare as a competing event (since treatments administered for flares could influence the duration of B cell depletion).