LAUSR

Background: Rituximab (RTX) was approved in patients with anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV). Objectives: To describe the pharmacokinetics of rituximab in AAV patients and to explore its sources of variability Methods: Rituximab pharmacokinetics was described in 92 AAV patients from the RAVE trial (rituximab for ANCA- associated vasculitis) using a population modeling approach. A semi-mechanistic model including a latent target antigen turnover allowed the estimation of specific target-mediated elimination of rituximab in addition to its non-specific elimination. Sex, body surface area (BSA), BVAS/WG score, and status newly diagnosed on pharmacokinetic parameters were investigated as covariates. Results: A two compartments model including target mediated elimination best described rituximab pharmacokinetics. The mean (interindividual standard deviation) estimated central volume of distribution was 3.06 L (2.61%), systemic clearance was 0.135 L days−1 (6.43%), and target-mediated elimination rate constant was 19.13 x 10-6 nmol-1 days−1(fixed to 0). The initial activity of the disease was higher in male than in female (p=4.09 x 10-14), and in patients newly diagnosed at inclusion (p=7.91 x 10-5). Moreover, systemic clearance was slightly lower in granulomatosis with polyangiitis group than in other AAV groups (p=3.6 x 10-3). Neither BVAS/WG score nor BSA were significant covariates in a multivariate analysis. Conclusion: We report a nonlinear target-mediated elimination of rituximab in AAV patients. Granulomatosis with polyangiitis patients have a lower global clearance of rituximab than other AAV groups. Our study not support the utility of BSA based individualized dosing protocols, as previously reported (1). Reference: [1] Cornec D, et al. Pharmacokinetics of rituximab and clinical outcomes in patients with anti-neutrophil cytoplasmic antibody associated vasculitis. Rheumatology. 2018;57:639-50. Disclosure of Interests: Denis Mulleman Speakers bureau: Pfizer, Novartis, Grifols, Amina Bensalem: None declared, David Ternant Speakers bureau: Sanofi, Amgen, Gilles Paintaud Grant/research support from: Novartis, Roche Pharma, Sanofi-Genzyme, Chugai, Pfizer and Shire, Divi Cornec: None declared, Ulrich Specks: None declared