Exposure‐response modeling of tocilizumab in rheumatoid arthritis using continuous composite measures and their individual components

Abstract

Aims: Tocilizumab has a direct effect on inflammatory markers. Therefore, composite measures for disease activity assessment in rheumatoid arthritis (RA) using these inflammatory markers may not be suitable for tocilizumab treatment. We used a modelling approach to describe the tocilizumab exposure-response relationship and to investigate the different dynamics of the individual components of the routinely used continuous composite measures.Methods: Pharmacokinetic (PK), clinical and laboratory data were obtained from a prospective, observational, single-centre study involving 35 subjects with RA treated with intravenous tocilizumab. A population PK/pharmacodynamic analysis was performed using nonlinear mixed effects models. Results: The population for model development comprised 1086, 1083 and 1082 observations calculated with the disease activity score based on 28 joint (DAS28) and the simplified and clinical disease activity scores (SDAI, CDAI). The tocilizumab exposure-response relationship was described with an indirect-response model. Two main groups of individual components were identified based on their different dynamics under tocilizumab treatment: (i) tender and swollen joint counts and patient and evaluator global assessment showed a slower decrease of their baseline value (half-life: 4.6 weeks, RSE: 24%) and the need for higher serum drug concentration (EC 50 : 4.60 μg/mL, RSE: 103%, IIV: 359%) than (ii) C-reactive protein and erythrocyte sedimentation rate (half-life: 2.3 weeks, RSE 19%; EC 50 : 0.878 μg/mL, RSE: 41%, IIV: 238%). Conclusion: Our study confirms a different dynamics of the individual components of the most frequently used continuous composite measures under tocilizumab treatment which should be taken into account to avoid misassessment of disease activity.

Modeling and Simulation to Support Phase Ib/IIa Dose Selection for WBP216, A Long Half-Life Fully Human Monoclonal Antibody Against Interleukin-6

“…As Table 2 shown, whatever K in,CRP or K out,CRP had greater value than those of DAS28, hinting high turnover rate of CRP. K in,DAS28 0.003 h −1 and K out,DAS28 6*10 −4 h −1 were very closed to reported values of tocilizumab (K in,DAS28 0.0037 h −1 ; K out,DAS28 7.2 × 10 −4 h −1 ) ( Bastida et al, 2019 ). While Levi et al reported K in,DAS28 0.011 h −1 and K out,DAS28 15.8 × 10 −4 h −1 using data from 4 phase III studies of tocilizumab, which was almost 2 fold of our estimated DAS28 parameters ( Levi et al, 2013 ).…”

“…Due to the blockade of IL-6 signaling, WBP216 can directly inhibit the hepatic production of C-reactive protein (CRP) directly ( Bastida et al, 2019 ) and the erythrocyte sedimentation rate (ESR). Thus, the levels of inflammatory markers (CRP and ESR) rapidly decrease after the initiation of IL-6 blocker treatment, even prior to any improvement in swollen or tender joint counts.…”

Relationship of C-Reactive Proteins and Erythrocyte Sedimentation Rate with Active Disease in Patients with Juvenile Rheumatoid Arthritis

“…Remission usually occurs in the first five years after the onset and is less common in patients with systemic onset and polyarticular JIA. Therefore, JRA is usually a disease that progresses into adulthood 12 . Compared to previous decades, functional outcomes have improved, but the estimated rate of arthroplasty is still very high.…”

Tocilizumab Trough Levels Variability in Kidney-Transplant Candidates Undergoing Desensitization

“…These findings must be interpreted with caution given the low number of patients of our cohort. Since several studies have reported a concentration-effect relationship for TCZ in rheumatoid arthritis [ 13 , 15 , 20 , 22 ], further research conducted in larger cohorts are needed to explore such a concentration-effect relationship when TCZ is used for desensitization.…”