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Towards Fixed Dosing of Tocilizumab in ICU-Admitted COVID-19 Patients: Results of an Observational Population Pharmacokinetic and Descriptive Pharmacodynamic Study.
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.
  • Moes DJAR; Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands. D.J.A.R.Moes@lumc.nl.
  • van Westerloo DJ; Leiden Network for Personalised Therapeutics, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands. D.J.A.R.Moes@lumc.nl.
  • Arend SM; Department of Intensive Care, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
  • Swen JJ; Department of Infectious Diseases, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
  • de Vries A; Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
  • Guchelaar HJ; Leiden Network for Personalised Therapeutics, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
  • Joosten SA; Biologics Lab, Sanquin Diagnostic Services, Plesmanlaan 125, 1066 CX, Amsterdam, The Netherlands.
  • de Boer MGJ; Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
  • van Gelder T; Leiden Network for Personalised Therapeutics, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
  • van Paassen J; Department of Infectious Diseases, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
Clin Pharmacokinet ; 61(2): 231-247, 2022 02.
Article in English | MEDLINE | ID: covidwho-1460524
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.
Subject(s)

Full text: Available Collection: International databases Database: MEDLINE Main subject: Antibodies, Monoclonal, Humanized / COVID-19 Drug Treatment Type of study: Experimental Studies / Observational study / Prognostic study / Randomized controlled trials Topics: Vaccines Limits: Adult / Humans Language: English Journal: Clin Pharmacokinet Year: 2022 Document Type: Article Affiliation country: S40262-021-01074-2

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antibodies, Monoclonal, Humanized / COVID-19 Drug Treatment Type of study: Experimental Studies / Observational study / Prognostic study / Randomized controlled trials Topics: Vaccines Limits: Adult / Humans Language: English Journal: Clin Pharmacokinet Year: 2022 Document Type: Article Affiliation country: S40262-021-01074-2