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.
Keywords: T-lymphocytes; pharmacodynamics; pharmacokinetics; rheumatoid arthritis; rituximab.
© 2019 The British Pharmacological Society.