POS1256 SINGLE DOSE TOCILIZUMAB PHARMACOKINETICS IN GLUCOCORTICOID PRE-TREATED COVID-19 PATIENTS DURING CYTOKINE STORM SYNDROME HYPERINFLAMMATORY EPISODE: LESS IS MORE
Authors: N. Boone, S. Ramiro, D. J. Moes, R. Mostard, C. Magro Checa, C. Van Dongen, M. Gronenschild, E. Van Haren, J. Buijs, R. Peeters, D. Wong, R. B. M. Landewé
Journal: Annals of the Rheumatic Diseases (2021)

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 &gt; 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) &gt;100 mg/L; ferritin &gt;900 μg/L; D-dimers &gt;1500 μg/L), received per protocol high-dose 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 Curve 0-∞ 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. Figure 1. Predicted concentration-time profiles after single dose tocilizumab in 34 methylpred-nisolone pretreated patients with COVID-19 induced cytokine storm syndrome. Dashed line: maximum IL-6 receptor occupancy concentration 1 µg/ml 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. References: [1]Ramiro S. Mostard R.L.M. et al. Historically controlled comparison of glucocorticoids with or without tocilizumab versus supportive care only in patients with COVID-19-associated cytokine storm syndrome: results of the CHIC study. Ann Rheum Dis 2020;79(9):1143-1151. [2]Nishimoto N, Terao K et al. Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease. Blood. 2008;112:3959-3964. Acknowledgements: The authors are grateful to all patients, nurses and physicians who participated in this study. Disclosure of Interests: None declared