CD4+ count‐dependent concentration–effect relationship of rituximab in rheumatoid arthritis. Issue 12 (22nd November 2019)

• Record Type: Journal Article
• Authors: Bensalem, Amina; Mulleman, Denis; Thibault, Gilles; Azzopardi, Nicolas; Goupille, Philippe; Paintaud, Gilles; Ternant, David
• Is Part Of: British journal of clinical pharmacology. Volume 85:Issue 12(2019)
• Page Start: 2747
• Page End: 2758
• Publication Date: 2019-11-22
• Subjects: pharmacodynamics -- pharmacokinetics -- rheumatoid arthritis -- rituximab -- T‐lymphocytes; Pharmacology -- Periodicals; Drugs -- Periodicals; 615.1
• DOI: 10.1111/bcp.14102
• Languages: English
• ISSNs: 0306-5251

Abstract

Abstract : Aims: Rituximab is approved in rheumatoid arthritis (RA). A substantial decrease in CD4+ count was observed in responders after a single cycle of treatment. This study aimed to describe and quantifying the influence of CD4+ count depletion on the concentration–response relationship of rituximab in RA patients. Methods: In this retrospective monocentric observational study, 52 patients were assessed. Repeated measurements of rituximab concentrations (pharmacokinetics), CD4+ counts (biomarker) and disease activity score in 28 joints (DAS28, clinical response) were made. Rituximab pharmacokinetics was described using a 2‐compartment model, and CD4+ cell counts and DAS28 measurements were described using indirect turnover and direct Emax pharmacokinetic–pharmacodynamic models, respectively. Delay between rituximab concentrations and responses was accounted for by including biophase compartments. Results: Elimination half‐life of rituximab was 18 days. The pharmacokinetic–pharmacodynamic model showed that DAS28 response to rituximab was partly associated with CD4+ cell depletion. At 6 months, a deeper DAS28 decrease was observed in patients when CD4+ cell count is decreased: median [interquartile range] of DAS28 was 3.7 [2.9–4.4] and 4.5 [3.7–5.3] in patients with and without CD4+ decrease, respectively. Conclusions: This is the first study to quantify the relationship between rituximab concentrations, CD4+ count and DAS28 in RA patients. This model showed that approximately 75% of patients had CD4+ count decrease, and that the clinical improvement is 2‐fold higher in patients with CD4+ cells decrease than in others.