Non-Linear Rituximab Pharmacokinetics and Complex Relationship between Rituximab Concentrations and Anti-Neutrophil Cytoplasmic Antibodies (ANCA) in ANCA-Associated Vasculitis: The RAVE Trial Revisited
Background and Objectives
Rituximab is approved in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and leads to a decrease of ANCA levels. The objectives of this study were to investigate the non-linear pharmacokinetics of rituximab and the relationship between its concentrations and ANCA levels in AAV patients.
Ninety-two AAV patients from the RAVE (Rituximab in ANCA-Associated Vasculitis) trial were assessed. Both ANCA anti-myeloperoxidase (MPO-ANCA) and anti-proteinase 3 (PR3-ANCA) levels were used as biomarkers. The pharmacokinetics of rituximab were described using a semi-mechanistic two-compartment model that included a latent target antigen turnover and allowed the estimation of specific target-mediated elimination in addition to its non-specific elimination of rituximab. The effect of rituximab on the ANCA level was described using a semi-mechanistic compartment model with a negative feedback (Friberg) model with no transit compartment. A population modeling approach was used.
Our pharmacokinetic and pharmacokinetic–pharmacodynamic (PK-PD) models satisfactorily described both concentration–time and concentration–effect relationship data. The mean (inter-individual standard deviation) estimated non-specific clearance was 0.15 L/day (0.30%) and the target-mediated elimination rate constant was 2.4 × 10−5 nmol/day. The elimination half-lives for MPO-ANCA and PR3-ANCA were 24 and 18 days, respectively.
A non-linear target-mediated elimination of rituximab was detected in AAV patients. Our PK-PD model allowed quantification of the association between rituximab concentrations and ANCA levels. This decrease was deep but delayed, and more sustained in patients with MPO-ANCA than in those with PR3-ANCA. Our results suggest that repeating courses of rituximab might improve the clinical response to rituximab.
The authors thank Melissa Cheu, Melissa R. Snyder, Amber M. Hummel, Carol A. Langford, Peter A. Merkel, Paul A. Monach, Philip Seo, Robert F. Spiera, E. William St Clair, Brian F. Kabat, John R. Mills, Darrell R. Schroeder, Matthew D. Cascino, Paul Brunetta, David L. Murray, Fernando Fervenza, and David R. Barnidge for acquiring the data. The authors thank John H. Stone, the principal investigator of the clinical study, for designing the study and acquiring the data.
AB analyzed and interpreted the data, and wrote the manuscript. DM initiated the study, participated in data interpretation, and reviewed the manuscript. US initiated the study, acquired the data, participated in data interpretation, and reviewed the manuscript. VG and GP proposed data investigation methods, participated in data interpretation, and reviewed the manuscript. NA participated in data interpretation and reviewed the manuscript. DC acquired the data, participated in data interpretation, and reviewed the manuscript. DT supervised data analysis and interpretation, manuscript redaction, and reviewed the manuscript.
Compliance with ethical standards
The RAVE (Rituximab in ANCA-Associated Vasculitis) trial, from which these data were obtained, was supported by a grant from the National Institute of Allergy and Infectious Diseases to the Immune Tolerance Network (grant N01-AI-15416; protocol no. ITN021AI). Genentech, Inc. and Biogen IDEC, Inc. provided the study medications and partial funding for the trial. Genentech, Inc. performed the rituximab concentration measurements by ELISA for the trial. The ANCA measurements by ELISA were performed at the Mayo Clinic using test kits provided by Euroimmun, Inc. Divi Cornec received fellowship grants from the French Society of Rheumatology and from Brest University Hospital, France. Ulrich Speck’s laboratory is supported by funds from the Connor Group Foundation and the Mayo Foundation. This work was partly supported by the French Higher Education and Research Ministry under the program ‘Investissements d’avenir’ (grant agreement: LabEx MAbImprove ANR-10-LABX-53-01).
Conflict of interest
Amina Bensalem, Nicolas Azzopardi, Valérie Gouilleux-Gruart, Divi Cornec, and Ulrich Specks have no conflicts of interest to declare. Denis Mulleman reports grants from Abbvie and Nordic Pharma, and consultancy fees from MSD, Novartis, UCB, and Pfizer. Gilles Paintaud reports grants received by his research team from Novartis, Roche Pharma, Genzyme, MSD, Chugai, and Pfizer. David Ternant reports lecture fees from Novartis, Amgen, and Boehringer Ingelheim.
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