Fixed dosing of intravenous tocilizumab in rheumatoid arthritis. Results from a population pharmacokinetic analysis

Bastida, Carla; Ruíz-Esquide, Virginia; Pascal, Mariona; Schultink, Aurelia H M de Vries; Yagüe, Jordi; Sanmartí, Raimón; Huitema, Alwin D. R.; Soy, Dolors

doi:10.1111/bcp.13500

Cited by 16 publications

(25 citation statements)

References 32 publications

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“…Additionally, serum CRP concentration was included in the propensity score matching. Furthermore, population pharmacokinetic analysis of tocilizumab supports a flat dosing approach due to reductions in the variability of drug exposure among patient weight categories 23 . Other limitations of our study include the retrospective design, as it may have increased the risk of selection bias toward more severe patients in the tocilizumab arm.…”

Section: Discussionmentioning

confidence: 97%

Impact of tocilizumab administration on mortality in severe COVID-19

Tsai

Diawara

Nahass

et al. 2020

Sci Rep

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The novel coronavirus disease 2019 (COVID-19) worldwide pandemic has placed a significant burden on hospitals and healthcare providers. The immune response to this disease is thought to lead to an aberrant inflammatory response or cytokine storm, which contributes to the severity of illness. There is an urgent need to confirm whether the use of tocilizumab provides a benefit in individuals with COVID-19. A single-center propensity-score matched cohort study, including all consecutive COVID-19 patients, admitted to the medical center who were either discharged from the medical center or expired between March 1, 2020, and May 5, 2020, was performed. Patients were stratified according to the receipt of tocilizumab for cytokine storm and matched to controls using propensity scores. The primary outcome was in-hospital mortality. A total of 274 patients meeting inclusion and exclusion criteria were identified and 132 patients were included in the matched dataset (tocilizumab = 66; no tocilizumab = 66). Approximately 73% of the patients were male. Hypertension (55%), diabetes mellitus (31%), and chronic pulmonary disease (15%) were the most common comorbidities present. There were 18 deaths (27.3%) in the tocilizumab group and 18 deaths (27.3%) in the no tocilizumab group (odds ratio, 1.0; 95% confidence interval, 0.465 – 2.151; p = 1.00). Advanced age, history of myocardial infarction, dementia, chronic pulmonary disease, heart failure, and malignancy were significantly more common in patients who died. The current analysis does not support the use of tocilizumab for the management of cytokine storm in patients with COVID-19. Use of this therapeutic agent should be limited to the context of a clinical trial until more evidence is available.

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Section: Discussionmentioning

confidence: 97%

Impact of tocilizumab administration on mortality in severe COVID-19

Tsai

Diawara

Nahass

et al. 2020

Sci Rep

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“…This study was based on data from a previously published PK study . Enrolled subjects received treatment for their RA with intravenous (iv) tocilizumab at an initial dose of 8 mg/kg every 28 days.…”

Section: Methodsmentioning

confidence: 99%

“…Models were parameterized in terms of fixed effects (population mean) and two levels of random effects: per subject (inter‐individual variability [IIV]) and per measurement (residual variability). The PPP&D (Population PK Parameters & Data) sequential approach using a previously published PK model, was chosen for the PKPD development.…”

Section: Methodsmentioning

confidence: 99%

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

Bastida

Soy

Ruíz-Esquide

et al. 2019

Brit J Clinical Pharma

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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.

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“…Furthermore, population pharmacokinetic analysis of tocilizumab supports a flat dosing approach due to reductions in the variability of drug exposure among patient weight categories. 22 Other limitations of our study include the retrospective design, as it may have increased the risk of selection bias toward more severe patients in the tocilizumab arm. While propensity score matching was utilized and resulted in well-matched groups, residual confounding cannot be excluded.…”

Section: Discussionmentioning

confidence: 99%

Impact of tocilizumab administration on mortality in severe COVID-19

Tsai

Diawara

Nahass

et al. 2020

Preprint

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Background The novel coronavirus disease 2019 (COVID-19) worldwide pandemic has placed a significant burden on hospitals and healthcare providers. The immune response to this disease is thought to lead to a cytokine storm, which contributes to the severity of illness. There is an urgent need to confirm whether the use of tocilizumab provides a benefit in individuals with COVID-19. Methods A single-center propensity-score matched cohort study, including all consecutive COVID-19 patients, admitted to the medical center who were either discharged from the medical center or expired between March 1, 2020, and May 5, 2020, was performed. Patients were stratified according to the receipt of tocilizumab for cytokine storm and matched to controls using propensity scores. The primary outcome was in-hospital mortality. Results A total of 132 patients were included in the matched dataset (tocilizumab=66; standard of care=66). Approximately 73% of the patients were male. Hypertension (55%), diabetes mellitus (31%), and chronic pulmonary disease (15%) were the most common comorbidities present. There were 18 deaths (27.3%) in the tocilizumab group and 18 deaths (27.3%) in the standard of care group (odds ratio, 1.0; 95% confidence interval, 0.465 - 2.151; p=1.00). Advanced age, history of myocardial infarction, dementia, chronic pulmonary disease, heart failure, and malignancy were significantly more common in patients who died. Interpretation The current analysis does not support the use of tocilizumab for the management of cytokine storm in patients with COVID-19. Use of this therapeutic agent should be limited to the context of a clinical trial until more evidence is available.

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Fixed dosing of intravenous tocilizumab in rheumatoid arthritis. Results from a population pharmacokinetic analysis

Abstract: Our study provides evidence to support fixed dosing of intravenous tocilizumab in rheumatoid arthritis patients since it reduces variability in tocilizumab exposure among weight categories compared to the current weight-based dosing approach.

Cited by 16 publications

References 32 publications

Impact of tocilizumab administration on mortality in severe COVID-19

Impact of tocilizumab administration on mortality in severe COVID-19

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

Impact of tocilizumab administration on mortality in severe COVID-19

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