Amina Bensalem (1), Denis Mulleman (1,2), Gilles Paintaud (1,3), Nicolas Azzopardi (1,4), Valérie Gouilleux-Gruart (1,5), Divi Cornec (6,7), Ulrich Specks (6), David Ternant (1,3).
(1) EA 7501 GICC, University of Tours, Tours, France, (2) Department of Rheumatology, CHRU de Tours, Tours, France, (3) Department of Medical Pharmacology, CHRU de Tours, Tours, France, (4) CNRS ERL 7001, Tours, France, (5) Laboratory of Immunology, CHRU de Tours, Tours, France, (6) Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA, (7) Rheumatology Department, Brest University Hospital, and INSERM U1227, Brest, France.
Objectives: Rituximab is approved in patients with anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV). Levels of antibodies to proteinase 3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA) are correlated with disease activity, decrease with treatment [1], and may therefore be used as biomarkers of response. The objectives of this study were to investigate the pharmacokinetics of rituximab and the relationship between rituximab concentration and ANCA levels in AAV patients.
Methods: Ninety-two AAV patients from the RAVE trial (rituximab for ANCA- associated vasculitis) were assessed [2]. Blood samples were collected at baseline, at weeks 2, at month 1, 2, 4, 6, 9, 12, 15 and18, and every 6 months until the end of follow-up. Rituximab concentrations were measured using a validated enzyme-linked immunosorbent assay (ELISA) by Genentech. Concentrations were not available at months 12 and 15. Levels of both MPO-ANCA and PR3-ANCA were measured using an ELISA supplied by Euroimmun. Pharmacokinetics of rituximab was described using a semi-mechanistic model that included a latent target antigen turnover and allowed the estimation of both target-mediated elimination and non-specific elimination. Concentration-ANCA relationship was described using semi-mechanistic Friberg models [3] that included a blood compartment, where ANCA concentrations are measured, and a production compartment that was sensitive to rituximab treatment and to negative feedback by blood ANCA. These models included 0, 1, 2 or 3 transit compartments. Pharmacokinetic and PK-PD parameters were estimated using nonlinear mixed-effects models with Monolix Suite 2018R2.
Results: A two-compartment model including target-mediated elimination best described pharmacokinetic data. A Friberg model [3] with no transit compartment best described the concentration-autoantibody relationship. Mean (interindividual standard deviation) estimated systemic clearance and target-mediated elimination rate constant were 0.15 L/days (7.7 %) and, 20.10-6 nmol-1 day-1, respectively. Concentrations of rituximab leading to 50% decrease of ANCA input in patients with MPO-ANCA and PR3-ANCA were 37.5 mg/L (29.3%) and 21.1 mg/L (34.7%), respectively.
Conclusions: This study is the first to describe rituximab pharmacokinetics in AAV using population PK-PD modeling approach. A nonlinear target-mediated elimination of rituximab was detected. Concentration-ANCA levels relationship was well described by a Friberg model with no transit compartment. The potency of rituximab in depleting ANCA input was higher in patients with PR3-ANCA than in patients with MPO-ANCA.
References:
[1] Fussner LA. et al. Factors Determining the Clinical Utility of Serial Measurements of Antineutrophil Cytoplasmic Antibodies Targeting Proteinase 3. Arthritis Rheumatol (2016).
[2] Stone JH. et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med (2010).
[3] Friberg LE. et al. Model of chemotherapy-induced myelosuppression with parameter consistency across drugs. J Clin Oncol (2002).
Reference: PAGE 28 (2019) Abstr 8931 [www.page-meeting.org/?abstract=8931]
Poster: Drug/Disease Modelling - Other Topics