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Pharmacokinetic/Pharmacodynamic Modeling of Dexamethasone Anti-Inflammatory and Immunomodulatory Effects in LPS-Challenged Rats: A Model for Cytokine Release Syndrome.
Swierczek, Artur; Jusko, William J.
  • Swierczek A; Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, New York.
  • Jusko WJ; Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, New York wjjusko@buffalo.edu.
J Pharmacol Exp Ther ; 384(3): 455-472, 2023 03.
Article in English | MEDLINE | ID: covidwho-2193368
ABSTRACT
Dexamethasone (DEX) is a potent synthetic glucocorticoid used for the treatment of variety of inflammatory and immune-mediated disorders. The RECOVERY clinical trial revealed benefits of DEX therapy in COVID-19 patients. Severe SARS-CoV-2 infection leads to an excessive inflammatory reaction commonly known as a cytokine release syndrome that is associated with activation of the toll like receptor 4 (TLR4) signaling pathway. The possible mechanism of action of DEX in the treatment of COVID-19 is related to its anti-inflammatory activity arising from inhibition of cytokine production but may be also attributed to its influence on immune cell trafficking and turnover. This study, by means of pharmacokinetic/pharmacodynamic modeling, aimed at the comprehensive quantitative assessment of DEX effects in lipopolysaccharide-challenged rats and to describe interrelations among relevant signaling molecules in this animal model of cytokine release syndrome induced by activation of TLR4 pathway. DEX was administered in a range of doses from 0.005 to 2.25 mg·kg-1 in LPS-challenged rats. Serum DEX, corticosterone (CST), tumor necrosis factor α, interleukin-6, and nitric oxide as well as lymphocyte and granulocyte counts in peripheral blood were quantified at different time points. A minimal physiologically based pharmacokinetic/pharmacodynamic (mPBPK/PD) model was proposed characterizing the time courses of plasma DEX and the investigated biomarkers. A high but not complete inhibition of production of inflammatory mediators and CST was produced in vivo by DEX. The mPBPK/PD model, upon translation to humans, may help to optimize DEX therapy in patients with diseases associated with excessive production of inflammatory mediators, such as COVID-19. SIGNIFICANCE STATEMENT A mPBPK/PD model was developed to describe concentration-time profiles of plasma DEX, mediators of inflammation, and immune cell trafficking and turnover in LPS-challenged rats. Interrelations among DEX and relevant biomarkers were reflected in the mechanistic model structure. The mPBPK/PD model enabled quantitative assessment of in vivo potency of DEX and, upon translation to humans, may help optimize dosing regimens of DEX for the treatment of immune-related conditions associated with exaggerated immune response.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Lipopolysaccharides / COVID-19 Type of study: Experimental Studies / Prognostic study / Randomized controlled trials Limits: Animals / Humans Language: English Journal: J Pharmacol Exp Ther Year: 2023 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Lipopolysaccharides / COVID-19 Type of study: Experimental Studies / Prognostic study / Randomized controlled trials Limits: Animals / Humans Language: English Journal: J Pharmacol Exp Ther Year: 2023 Document Type: Article