Single dose tocilizumab pharmacokinetics in glucocorticoid pre-treated COVID-19 patients during cytokine storm syndrome hyperinflammatory episode: Less is more

Boone, N.; Ramiro, S.; Moes, D. J.; Mostard, R.; Magro Checa, C.; Van Dongen, C.; Gronenschild, M.; Van Haren, E.; Buijs, J.; Peeters, R.; Wong, D.; Landewé, R. B. M.

Background: The cytokine storm syndrome (CSS) associated with COVID-19 pneumonia occurs in up to 20% of the admitted patients causing high morbidity and mortality [1]. In the COVID High-intensity Immunosuppression in Cytokine storm syndrome (CHIC) study [1] we reported that CSS patients, who despite high-dose methylprednisolone (MP) treatment still showed severe respiratory deterioration, received subsequent single dose tocilizumab (TCZ) treatment. Our clinical experience with TCZ, every 4 weeks in RA, where a pre-dose serum concentration of ≥ 1 μg/ml is sufficient to block all interleukin (IL)-6 receptors and thereby induce and maintain clinical remission, prompted further investigation of TCZ pharmacokinetics in patients with COVID-19 CSS [1,2]. Objectives: In this pharmacokinetic study we investigated the clinical-pharmacokinetic rationale for a single TCZ dose in a subset of COVID19 induced CSS patients. Methods: Patients with COVID-19-associated CSS, defined as rapid respiratory deterioration plus at least two biomarker elevations (C-reactive protein (CRP) ≥100 mg/L;ferritin ≥900 μg/L;D-dimers ≥1500 μg/L), received per protocol highdose intravenous MP for 5 consecutive days. If the respiratory condition had not improved sufficiently, TCZ (8 mg/kg, max. 800 mg) single infusion was added on or after day 2[1]. TCZ serum samples were drawn at TCZ day 1, 3 and 10 to assess TCZ serum concentrations with a validated ELISA-method. A nonlinear-mixed effects model was developed based on all concentration time data to characterise TCZ pharmacokinetics (NONMEM). Subsequently individual pharmacokinetic parameters (AUC0-inf, Cmax, time above 1 μg/ml) were estimated and TCZ concentration-time observations were plotted against the individual predicted concentrations to visualize the complete TCZ concentration-time curve. Results: In total, 34 patients with COVID19 induced CSS still showing clinical deterioration upon MP treatment received TCZ per protocol [mean (SD) age: 62 (12) years, 22% female, baseline mean (SD) bodyweight: 87 (17) kg, CRP: 108 (833) mmol/L, ferritin: 1653 (911) μg/L, D-dimers 4462 (7272) μg/L]. TCZ clearance was described by a homogeneous population-kinetics model yielding 87 serum samples. TCZ serum concentrations followed a biphasic course [Distribution volume 5.0 L (3.3-7.3), Area Under the Curve0-∞1st dose (682 (397-913) mg/L∗days), Cmax 137 mg/L (88 -199), half-life (linear) 3.5 days (2.3-4.1)]. In all patients, TCZ serum concentrations remained above the theoretical maximum IL-6 receptor occupancy concentration of 1 μg/ml for at least 12 days, depicted in Figure 1. Conclusion: Based on our study results on the pharmacokinetics of TCZ in patients with severe COVID-19 induced CSS we conclude that the clearance of TCZ is faster compared to RA-patients at steady state. However, our observations indicate that a single dose of tocilizumab in CSS-patients is enough to cover IL-6 mediated hyperinflammation. Restricting TCZ to a single dosage can prevent overtreatment, drug shortage and saves costs, while still maintaining efficacy, as most patients will have overcome their hyperinflammatory period of the CSS after 10-14 days.