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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

20 Pages Posted: 8 May 2021

See all articles by Dirk Jan Moes

Dirk Jan Moes

Leiden University - Department of Clinical Pharmacy and Toxicology

David van Westerloo

Leiden University - Department of Intensive Care

Sandra Arend

Leiden University - Department of Infectious Diseases

Jesse Swen

Leiden University - Department of Clinical Pharmacy and Toxicology

Annick De Vries

Sanquin Diagnostic Services - Biologics Lab

Henk-Jan Guchelaar

Leiden University - Department of Clinical Pharmacy and Toxicology

Simone Joosten

Leiden University - Department of Infectious Diseases

Mark De Boer

Leiden University - Department of Infectious Diseases

Teun Van Gelder

Leiden University - Department of Clinical Pharmacy and Toxicology

Judith van Paassen

Leiden University - Department of Intensive Care

More...

Abstract

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.

Findings: 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 1st DOSE was 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.

Interpretation: 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.

Declaration of Interests: N.A.

Ethics Approval Statement: The study was conducted in compliance with the Declaration of Helsinki and approved by the COVID-19 scientific and ethics committee of the Leiden University Medical Center with number coco 2020-033. Furthermore a waiver for the requirement for informed consent was granted.

Suggested Citation

Moes, Dirk Jan and van Westerloo, David and Arend, Sandra and Swen, Jesse and De Vries, Annick and Guchelaar, Henk-Jan and Joosten, Simone and De Boer, Mark and Van Gelder, Teun and van Paassen, Judith, 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. Available at SSRN: https://ssrn.com/abstract=3835128 or http://dx.doi.org/10.2139/ssrn.3835128

Dirk Jan Moes (Contact Author)

Leiden University - Department of Clinical Pharmacy and Toxicology ( email )

Leiden
Netherlands

David Van Westerloo

Leiden University - Department of Intensive Care ( email )

Albinusdreef 2
Leiden, South Holland 2333 ZA
Netherlands

Sandra Arend

Leiden University - Department of Infectious Diseases ( email )

Netherlands

Jesse Swen

Leiden University - Department of Clinical Pharmacy and Toxicology ( email )

Leiden
Netherlands

Annick De Vries

Sanquin Diagnostic Services - Biologics Lab ( email )

Amsterdam
Netherlands

Henk-Jan Guchelaar

Leiden University - Department of Clinical Pharmacy and Toxicology ( email )

Leiden
Netherlands

Simone Joosten

Leiden University - Department of Infectious Diseases ( email )

Netherlands

Mark De Boer

Leiden University - Department of Infectious Diseases ( email )

Netherlands

Teun Van Gelder

Leiden University - Department of Clinical Pharmacy and Toxicology ( email )

Leiden
Netherlands

Judith Van Paassen

Leiden University - Department of Intensive Care ( email )

Albinusdreef 2
Leiden, South Holland 2333 ZA
Netherlands

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