(T-102) Methylprednisolone PK/PD in a Rat Model of Cytokine Release Syndrome

William Jusko – Pharmaceutical Sciences – University at Buffalo; Wensi Wu – Pharmaceutical Sciences – University at Buffalo; Nitheesh Yanamandala – Pharmaceutical Sciences – University at Buffalo

Objectives: Cytokine release syndrome (CRS) is a systemic inflammatory response triggered by various factors, including viruses, bacteria, sepsis, autoinflammatory disease, and CAR-T therapy with adverse effects ranging from mild fever to organ failure [1]. CRS is driven by elevated cytokines including interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α) as well as nitric oxide (NO) [1] [2]. CRS is treated with corticosteroids such as methylprednisolone (MPL) due to its anti-inflammatory properties [3]. Pharmacokinetic (PK)/pharmacodynamic (PD) modeling was used to assess MPL disposition and effects in lipopolysaccharide (LPS)-challenged rats. In addition to plasma, the PK and inflammatory biomarkers were examined in the CRS-damaging targets, heart and lung.

Methods: Male Wistar rats were given 5.0 mg/kg LPS intraperitoneally to induce CRS [4]. MPL was dosed SC at 0 (control) and 0.05, 0.5, 2, 10, and 15 mg/kg. Plasma, heart, and lung were collected at various times over 48 h for MPL and biomarker analysis. MPL was quantified via LC-MS, IL-6 and TNF-α via ELISA, and NO via a chemical assay. PK/PD modeling was performed using ADAPT5.

Results: The PK of MPL in LPS-challenged rats exhibited biexponential disposition with modest nonlinearity, dose-dependent initial slopes, and prolonged terminal phases. Tissue analysis revealed high tissue-to-plasma partition coefficients (Kp) in both heart and lung with nonlinearity in lung. IL-6 and TNF-α in plasma exhibited dose-dependent suppression with MPL over 8 h, while NO produced suppression over 48 hours. AUC values for IL-6 and TNF-α decreased with increasing MPL doses, whereas NO suppression appeared all-or-none. Cytokine and NO concentrations in heart and lung were strongly elevated by LPS over 48 h (10-fold higher than plasma), but clear responsiveness to MPL was not found.

Conclusions: A two-compartment model with nonlinear distribution clearance best reflected MPL PK. The nonlinearity in Kp and long terminal half-life of MPL is consistent with binding to glucocorticoid receptors and 11β-hydroxysteroid dehydrogenase. While MPL strongly suppressed cytokines and NO in plasma with low IC50 values, minimal effects were found in heart and lung. These studies confirm the usefulness of measuring plasma but not tissue biomarkers in this animal model of CRS. The modeling results can be compared to similar studies with dexamethasone [5], the other main corticosteroid used to treat CRS.

Citations: [1] Shimabukuro-Vornhagen, A., et al., Cytokine release syndrome. J Immunother Cancer, 2018. 6(1): p. 56.
[2] Tang, X.D., et al., Pathogenesis and Treatment of Cytokine Storm Induced by Infectious Diseases. Int J Mol Sci, 2021. 22(23).
[3] Ranjbar, K., et al., Methylprednisolone or dexamethasone, which one is superior corticosteroid in the treatment of hospitalized COVID-19 patients: a triple-blinded randomized controlled trial. BMC Infect Dis, 2021. 21(1): p. 337.
[4] Domscheit, H., et al., Molecular Dynamics of Lipopolysaccharide-Induced Lung Injury in Rodents. Front Physiol, 2020. 11: p. 36.
[5] Świerczek, A. and W.J. Jusko, Pharmacokinetic/Pharmacodynamic Modeling of Dexamethasone Anti-Inflammatory and Immunomodulatory Effects in LPS-Challenged Rats: A Model for Cytokine Release Syndrome. J Pharmacol Exp Ther, 2023. 384(3): p. 455-472.

Keywords: Cytokine release syndrome