Dirk Jan A.R. Moes (1,2), David J. van Westerloo (3), Sandra M. Arend (4), Jesse J. Swen (1,2), Annick de Vries (5), Henk-Jan Guchelaar (1,2), Simone A. Joosten (4), Mark G.J. de Boer (4), Teun van Gelder (4), Judith van Paassen (3)
(1) Leiden University Medical Center, Department of Clinical Pharmacy and Toxicology, The Netherlands, (2) Leiden Network for Personalised Therapeutics, The Netherlands, (3)Leiden University Medical Center, Department of Intensive Care, The Netherlands, (4) Leiden University Medical Center, Department of Infectious Diseases, The Netherlands, (5) Biologics Lab, Sanquin Diagnostic Services, Plesmanlaan 125, The Netherlands
Introduction: The inflammatory storm associated with severe acute respiratory syndrome coronavirus 2 infection damages the respiratory tract and causes high morbidity and mortality [1]. In the randomized controlled trial REMAP-CAP, it was shown that next to dexamethasone, the IL-6 receptor antagonist tocilizumab improves outcome, including survival in ICU admitted COVID-19 patients [2,3]. 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. 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. The currently applied dosage of 8 mg/kg is based on use of this drug for other indications. In this study the pharmacokinetics and dynamics of tocilizumab were investigated in ICU admitted COVID-19 patients.
Objectives: The primary objective of this study was to characterize the population pharmacokinetics and pharmacodynamics of tocilizumab in ICU admitted COVID-19 patients.
The secondary objective of this study was to identify potential covariates that influence the pharmacokinetics of tocilizumab and to develop an alternative dosing recommendation for tocilizumab ICU admitted COVID-19 patients.
Methods: This was an open-label, single-center observational pharmacokinetic and -dynamic evaluation study. Enrolled adult 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 received tocilizumab within 24 hours after admission to the ICU and received 6 mg dexamethasone daily as concomitant therapy. A nonlinear mixed effects model was developed to characterize the pharmacokinetics parameters of tocilizumab in ICU admitted COVID-19 patients. Tocilizumab plasma concentrations were determined with a validated ELISA method. Plasma sIL-6R was determined by ELISA in duplicate using the commercial Quantikine Human IL-6sR kit. Covariate analysis was performed to identify potential covariates such as baseline demographic covariates (gender, bodyweight, age, BMI, BSA, height) and laboratory covariates for dose individualization. For the development of alternative dosing schedules Monte Carlo simulations using the final model were performed.
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. Tocilizumab plasma concentration data were best described by a one-compartment disposition model with parallel first order (linear) and Michaelis–Menten (nonlinear) elimination kinetics. Average CL was estimated to be 0.725 L/Day, average Vd was 4.34 L. Vmax was 4.19 ug/day and Km was 0.22 ug/ml). Interindividual variability was identified for CL (18.9%) and Vd (21%). Residual variability was characterized by a combined error model with an additive error of 0.139 μg/ml and a proportional error of 17.1% (expressed as the coefficient of variation). 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. The baseline demographic covariates (gender, bodyweight, age, BMI, BSA, height) and laboratory covariates (creatinine, eGFR, urea, albumin, LDH, ASAT, ALAT, GGT, total bilirubin, albumin, CRP) did not show any relationship between clearance or distribution volume. In all patients CRP declined rapidly after tocilizumab administration and remained low for at least ten days. Bodyweight based dosing increases variability in exposure compared to fixed dosing. Repeated dosing with lower dosages (and lower cumulative dosages) results in longer durations of tocilizumab exposure above the saturation thresholds compared to a single high dose of 800 mg.
Conclusions: 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.
References:
[1] Hu B, Guo H, Zhou P, Shi ZL. Characteristics of SARS-CoV-2 and COVID-19. Nat Rev Microbiol. 2021;19(3):141-54.
[2] Group WHOREAfC-TW, Sterne JAC, Murthy S, Diaz JV, Slutsky AS, Villar J, et al. Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis. JAMA. 2020;324(13):1330-41.
[3] Investigators R-C, Gordon AC, Mouncey PR, Al-Beidh F, Rowan KM, Nichol AD, et al. Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19. N Engl J Med. 2021.
Reference: PAGE 29 (2021) Abstr 9637 [www.page-meeting.org/?abstract=9637]
Poster: Drug/Disease Modelling - COVID-19