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

• Published in: Clinical pharmacokinetics 2022-02, Vol.61 (2), p.231-247
• Main 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
• Format: Article
• Language: English
• Subjects: Adult; Antibodies, Monoclonal, Humanized - administration & dosage; Clinical trials; Coronaviruses; COVID-19; COVID-19 - drug therapy; Cytokines; Drug dosages; FDA approval; Humans; Intensive care; Intensive Care Units; Internal Medicine; Medicine; Medicine & Public Health; Monoclonal antibodies; Original; Original Research Article; Pharmacodynamics; Pharmacokinetics; Pharmacology/Toxicology; Pharmacotherapy; Plasma; Polymerase chain reaction; Population; Sample size; SARS-CoV-2; Severe acute respiratory syndrome coronavirus 2; Ventilators
• ISSN: 0312-5963; 1179-1926
• DOI: 10.1007/s40262-021-01074-2

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 ( V d ) was 4.34 L, maximum elimination rate ( V max ) was 4.19 μg/day, and concentration at which the elimination pathway is half saturated ( K m ) was 0.22 μg/mL. Interindividual variability was identified fo