Fixed dosing of tocilizumab in ICU admitted COVID-19 patients is a superior choice compared to bodyweight based dosing; an observational population pharmacokinetic and pharmacodynamic study
Authors: Moes Dirk Jan A.R. , van Westerloo David J. , Arend Sandra M. , Swen Jesse J. , de Vries Annick , Guchelaar Henk-Jan , Joosten Simone A. , de Boer Mark G.J. , van Gelder Teun , van Paassen Judith 
Published: May 2021

Background

Tocilizumab improves outcome, including survival, in intensive care unit (ICU) admitted COVID-19 patients. The currently applied dosage of 8 mg/kg is based on use of this drug for other indications, however is has not formally been investigated for COVID-19. In this study pharmacokinetics and dynamics of tocilizumab were investigated in ICU admitted COVID-19 patients.

Methods

This was an open-label, single-center observational pharmacokinetic and -dynamic evaluation study. Enrolled patients, with polymerase chain reaction confirmed Covid-19 were admitted to the ICU for mechanical ventilation or high flow nasal canula oxygen support. All patients were 18 years of age or older and received tocilizumab within 24 hours after admission to the ICU and received 6 mg dexamethasone daily as concomitant therapy.

Results

29 patients were enrolled between 15 December 2020 and 15 March 2021. A total of 139 tocilizumab plasma samples were obtained covering the pharmacokinetic curve of day 0 up to day 20 after tocilizumab initiation. A population pharmacokinetic model with parallel linear and non-linear clearance was developed and validated. Average AUC0-inf 1stDOSEwas 938 [±190] ug/mL*days. Tocilizumab half-life was estimated to be 4·15 [±0·24] days. All patients had tocilizumab exposure above 1 ug/ml for at least 15 days.

Conclusion

This study provides evidence to support a fixed dose of 600 mg tocilizumab in COVID-19 patients. Furthermore our findings suggest that alternative cost saving regimens with even lower doses are likely to be as effective as the current 8 mg/kg recommendation.

Funding

No external funding was received for this work

Background

In the randomized controlled trial REMAP-CAP, the IL-6 receptor antagonist tocilizumab was shown to improve outcome, including survival in ICU admitted COVID-19 patients. Because obesity is a risk factor for development of severe COVID-19, concerns have been raised about overtreatment as well as undertreatment through weight-based dosing of tocilizumab. Furthermore pharmacokinetic and pharmacodynamic parameters of medications are often found to be different in severely ill patients when compared to mild or moderately ill patients. However, the effects of different dosing schedules were only investigated to a very limited extent in non-randomized observational studies. Hence, evaluation of the PK/PD parameters of tocilizumab in severely ill patients – is warranted.

Added value of this study

This study provides valuable information about the population pharmacokinetics and dynamics of tocilizumab in dexamethasone cotreated ICU admitted COVID-19 patients. This research shows that there is no rationale for the 8 mg/kg dosing recommendation in ICU patients. Fixed dosing of 600 mg tocilizumab is a cost saving, logistically attractive and safe alternative without losing efficacy.

Implications of all the evidence

Due to the ongoing pandemic, shortages of tocilizumab and other IL-6 receptor antagonists may be anticipated. A fixed tocilizumab dose regimen has many practical and safety advantages, e.g. it will reduce dosing errors and avoid unnecessary wastage of medication. More importantly, according to the data presented in this study, relative underdosing of patients with low, or low-normal bodyweight compared to patients with high bodyweight will be avoided. Last but not least, in view of the large number of patients currently being treated with these agents, a significant cost saving can also be expected.