Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, New York.
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, New York
J Pharmacol Exp Ther. 2023 Mar;384(3):455-472. doi: 10.1124/jpet.122.001477. Epub 2023 Jan 11.
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 in LPS-challenged rats. Serum DEX, corticosterone (CST), tumor necrosis factor , 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.
地塞米松（DEX）是一种强效合成糖皮质激素，用于治疗多种炎症和免疫介导的疾病。RECOVERY 临床试验表明 DEX 治疗 COVID-19 患者有益。严重的 SARS-CoV-2 感染会导致过度的炎症反应，通常称为细胞因子释放综合征，这与 Toll 样受体 4（TLR4）信号通路的激活有关。DEX 治疗 COVID-19 的可能作用机制与其抗炎活性有关，这种抗炎活性源于抑制细胞因子的产生，但也可能与其对免疫细胞迁移和更新的影响有关。本研究通过药代动力学/药效动力学建模，旨在全面定量评估 DEX 在脂多糖（LPS）挑战大鼠中的作用，并描述 TLR4 通路激活诱导的细胞因子释放综合征动物模型中相关信号分子之间的相互关系。在 LPS 挑战大鼠中，DEX 以 0.005 至 2.25 mg·kg 的剂量范围给药。在不同时间点定量测定血清 DEX、皮质酮（CST）、肿瘤坏死因子、白细胞介素-6 和一氧化氮以及外周血中的淋巴细胞和粒细胞计数。提出了一个最小生理基于药代动力学/药效动力学（mPBPK/PD）模型，用于描述血浆 DEX 和研究生物标志物的时间过程。DEX 在体内产生了对炎症介质和 CST 产生的高但不完全的抑制作用。mPBPK/PD 模型在转化为人类后，可能有助于优化 COVID-19 等炎症介质过度产生相关疾病患者的 DEX 治疗。意义陈述：建立了一个 mPBPK/PD 模型，用于描述 LPS 挑战大鼠血浆 DEX、炎症介质和免疫细胞迁移和更新的浓度-时间曲线。DEX 与相关生物标志物之间的相互关系反映在机制模型结构中。mPBPK/PD 模型能够定量评估 DEX 的体内效力，转化为人类后，可能有助于优化 DEX 治疗与过度免疫反应相关的免疫相关疾病的剂量方案。
