Premium
CD4+ count‐dependent concentration–effect relationship of rituximab in rheumatoid arthritis
Author(s) -
Bensalem Amina,
Mulleman Denis,
Thibault Gilles,
Azzopardi Nicolas,
Goupille Philippe,
Paintaud Gilles,
Ternant David
Publication year - 2019
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.14102
Subject(s) - rituximab , rheumatoid arthritis , medicine , interquartile range , pharmacodynamics , pharmacokinetics , biomarker , rheumatology , gastroenterology , immunology , lymphoma , chemistry , biochemistry
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.