Amina Bensalem (1), Denis Mulleman (1,2), Gilles Thibault (1,3,4), Nicolas Azzopardi(1,4), Gilles Paintaud (1,5), Philippe Goupille (1,2), David Ternant (1,5).
(1) EA GICC, University of Tours, Tours, France, (2) Department of Rheumatology, CHRU de Tours, Tours, France, (3) Laboratory of Immunology, CHRU de Tours, Tours, France, (4) CNRS ERL 7001, Tours, France, (5) Laboratory of Pharmacology-Toxicology, CHRU de Tours, Tours, France.
Objectives: Rituximab (RTX) is approved as a second line treatment in active rheumatoid arthritis (RA) in combination with methotrexate, but there is a large inter-individual variability in clinical response. A better response was previously associated with a decrease in CD4+ T cell counts [1, 2]. However, no PK–PD study of RTX in RA is available. This study aimed at quantifying the contribution of CD4+ T cell decrease in the clinical response in RA patients treated with RTX.
Methods: In this retrospective monocentric observational study, 52 patients were assessed. All patients had received 2 infusions of 1000 mg of RTX 2 weeks apart. Peripheral blood CD4+ counts and disease activity score in 28 joints (DAS28) were used as biomarker of effect and modeled as a dependent variable. RTX serum concentrations, peripheral blood CD4+ counts, and DAS28 were measured before and after each RTX infusion and at 3, 6 and 9 months after last infusion. A population PK-PD model was developed using Monolix Suite 2016R1, where a between-subject model mixtures (BSMM) was implemented to well describe the clinical response in patients with and without CD4+ cell decrease and estimate the probability of CD4+ counts decrease. A turnover model was used to describe the effect of RTX on CD4+ T-cell counts, whereas a direct model was used to describe both RTX and CD4 + T cell count effect on DAS28.
Results: Our PK–PD model described the data satisfactorily. The probability of CD4+ counts decrease was estimated at 0.75. Patients with a CD4+ decrease had a higher ∆DAS28 than the patients without CD4+ decrease, with a maximal ∆DAS28 of -1.34 and -0.64 in patients with and without CD4+ cell decrease, respectively. Moreover, at M6, patients with CD4+ cell decrease had a median DAS28 of 3.5 (IQR: 2.7 – 4.4), among them 39.5 % with low disease activity (DAS28≤ 3.2) and 22.3 % in remission (DAS28< 2.6). At the same time point, median DAS28 of patients without CD4+ cell decrease was 4.3 (IQR: 3.5 – 5.1), among them 17.7 % with low disease activity, and 8.6 % in remission.
Conclusions: This is the first study describing concentration-effect relationship of RTX in RA patients, using well-defined biological and clinical outcomes, as measured by CD4+ counts and DAS28 respectively. Our results confirmed that clinical improvement of RA patients after RTX treatment is partly dependent on the mechanism of CD4+ cells, and quantified the proportion of both RTX concentration and CD4 counts that induces DAS28 decrease.
References:
[1] Melet J. et al. Rituximab-induced T cell depletion in patients with rheumatoid arthritis: association with clinical response. Arthritis Rheum (2013).
[2] Lavielle M. et al. Repeated decrease of CD4+ T-cell counts in patients with rheumatoid arthritis over multiple cycles of rituximab treatment. Arthritis Res Ther (2016).
Reference: PAGE 27 (2018) Abstr 8477 [www.page-meeting.org/?abstract=8477]
Poster: Drug/Disease Modelling - Other Topics