Towards Fixed Dosing of Tocilizumab in ICU-Admitted COVID-19 Patients: Results of an Observational Population Pharmacokinetic and Descriptive Pharmacodynamic Study.

Abstract

BACKGROUND AND OBJECTIVE:

In the randomized controlled trial REMAP-CAP, it was shown that next to dexamethasone, the interleukin (IL)-6 receptor antagonist tocilizumab improves outcome, including survival in intensive care unit (ICU)-admitted coronavirus disease 2019 (COVID)-19 patients. Therefore tocilizumab has been added to many COVID-19 treatment guidelines. Because obesity is a risk factor for the development of severe COVID-19, concerns have been raised about overtreatment, as well as undertreatment, through weight-based dosing of tocilizumab. The currently applied dose of 8 mg/kg is based on the use of this drug for other indications, however it has not formally been investigated for COVID-19. In this study, the pharmacokinetics and pharmacodynamics of tocilizumab were investigated in ICU-admitted COVID-19 patients.

METHODS:

This was an open-label, single-centre, observational population pharmacokinetic and descriptive pharmacodynamic 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 intravenous tocilizumab 8 mg/kg (maximum 800 mg) within 24 h after admission to the ICU and received dexamethasone 6 mg daily as concomitant therapy. For evaluation of the pharmacokinetics and pharmacodynamics of tocilizumab, all time points from day 0 to 20 days after dose administration were eligible for collection. A nonlinear mixed-effects model was developed to characterize the population pharmacokinetic parameters of tocilizumab in ICU-admitted COVID-19 patients. Covariate analysis was performed to identify potential covariates for dose individualization. For the development of alternative dosing schedules, Monte Carlo simulations using the final model were performed.

RESULTS:

Overall, 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 to day 20 after tocilizumab initiation. A population pharmacokinetic model with parallel linear and nonlinear clearance (CL) was developed and validated. Average CL was estimated to be 0.725 L/day, average volume of distribution (Vd) was 4.34 L, maximum elimination rate (Vmax) was 4.19 μg/day, and concentration at which the elimination pathway is half saturated (Km) was 0.22 μg/mL. Interindividual variability was identified for CL (18.9%) and Vd (21%). Average area under the concentration versus time curve from time zero to infinity of the first dose (AUCinf 1st DOSE) was 938 [±190] μg/mL*days. All patients had tocilizumab exposure above 1 μg/mL for at least 15 days. Bodyweight-based dosing increases variability in exposure compared with fixed dosing.

CONCLUSIONS:

This study provides evidence to support a fixed dose of tocilizumab 600 mg in COVID-19 patients. Fixed dosing is a safe, logistically attractive, and drug expenses saving alternative compared with the current 8 mg/kg recommendation.

• Authors: Dirk Jan A R Moes, David J van Westerloo, Sandra M Arend, Jesse J Swen, Annick de Vries, Henk-Jan Guchelaar, Simone A Joosten, Mark G J de Boer, Teun van Gelder, Judith van Paassen
• Journal: Clinical pharmacokinetics (Clin Pharmacokinet) Vol. 61 Issue 2 Pg. 231-247 (02 2022) ISSN: 1179-1926 [Electronic] Switzerland
• PMID: 34633645 (Publication Type: Journal Article, Observational Study)
• Copyright: © 2021. The Author(s).

Chemical References

• Antibodies, Monoclonal, Humanized
• tocilizumab

Topics

• Adult
• Antibodies, Monoclonal, Humanized (administration & dosage)
• Humans
• Intensive Care Units
• SARS-CoV-2
• COVID-19 Drug Treatment