利用基于生理学的药代动力学模型揭示 COVID-19 介导的 CYP3A4 双向失调对全身和肺部药物浓度的影响

IF 4.4 3区 医学 Q1 PHARMACOLOGY & PHARMACY
Chukwunonso K Nwabufo
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引用次数: 0

摘要

多项临床研究表明,COVID-19 会增加 COVID-19 住院患者的全身药物浓度。然而,目前还不清楚 COVID-19 介导的肝脏和肺部 CYP3A4 双向调节失调如何影响药物浓度,尤其是在受疾病影响最大的肺组织中。在此,研究人员根据现有的 COVID-19 与 CYP3A4 相互作用的临床数据(包括门诊病人、非重症监护病房病人和重症监护病房病人),利用 PBPK 模型证明了当 CYP3A4 在肝脏同时下调、在肺部同时上调时,四种呼吸道传染病药物在全身和肺部的浓度差异。研究表明,尽管肝脏和肺部 CYP3A4 同时存在双向调节失调,但肝脏代谢是全身和肺部药物浓度的主要决定因素。与健康组相比,ICU 患者的全身和肺部药物暴露量最大,克拉霉素、尼尔马特韦、地塞米松和伊曲康唑的 AUCplasma 百分比分别增加了约 44%、56%、114% 和 196%。在重症监护室队列中,克拉霉素在肺组织中的暴露量最高,其折叠变化为 1189 倍,而尼尔马特韦和地塞米松在血浆中的暴露量最高,与目标病原体的最大治疗浓度相比,其折叠变化分别约为 126 倍和 5 倍。伊曲康唑在肺液中的暴露量明显不足,这可能是其治疗COVID-19疗效有限的原因。这些发现凸显了优化重症监护病房高危患者用药方案以提高疗效和安全性的重要性。意义声明 本研究调查了 COVID-19 介导的 CYP3A4 肝下调和肺上调是否同时导致四种呼吸系统药物的全身和肺部浓度差异。研究表明,药物浓度的室间差异仅由肝脏 CYP3A4 表达驱动。这项研究表明,具有显著 COVID-19 - CYP3A4 相互作用的 ICU 患者可能有发生临床相关的 COVID-19 - 药物相互作用的风险,这突出表明有必要优化该患者群体的给药方案,以提高安全性和疗效。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Uncovering the Impact of COVID-19 Mediated Bidirectional Dysregulation of CYP3A4 on Systemic and Pulmonary Drug Concentrations Using Physiologically Based Pharmacokinetic Modeling.

Several clinical studies have shown that COVID-19 increases the systemic concentration of drugs in hospitalized COVID-19 patients. However, it is unclear how COVID-19-mediated bidirectional dysregulation of hepatic and pulmonary CYP3A4 impacts drug concentrations, especially in the lung tissue which is most affected by the disease. Herein, PBPK modeling was used to demonstrate the differences in systemic and pulmonary concentrations of four respiratory infectious disease drugs when CYP3A4 is concurrently downregulated in the liver and upregulated in the lung based on existing clinical data on COVID-19 - CYP3A4 interactions at varying severity levels including outpatients, non-ICU, and ICU patients. The study showed that hepatic metabolism is the primary determinant of both systemic and pulmonary drug concentrations despite the concurrent bidirectional dysregulation of liver and lung CYP3A4. ICU patients had the most systemic and pulmonary drug exposure with a percentage increase in AUCplasma of approximately 44%, 56%, 114%, and 196% for clarithromycin, nirmatrelvir, dexamethasone, and itraconazole, respectively, relative to the healthy group. Within the ICU cohort, clarithromycin exhibited its highest exposure in lung tissue mass with a fold change of 1189, while nirmatrelvir and dexamethasone showed their highest exposure in the plasma compartment, with fold changes of about 126 and 5, respectively, compared to the maximum therapeutic concentrations for their target pathogens. Itraconazole was significantly under-exposed in the lung fluid compartment potentially explaining its limited efficacy for the treatment of COVID-19. These findings underscore the importance of optimizing dosing regimens in at risk ICU patients to enhance both efficacy and safety profiles. Significance Statement This study investigated whether COVID-19-mediated concurrent hepatic downregulation and pulmonary upregulation of CYP3A4 leads to differences in the systemic and pulmonary concentrations of four respiratory medicines. The study demonstrated that intercompartmental differences in drug concentrations were driven by only hepatic CYP3A4 expression. This work suggests that ICU patients with significant COVID-19 - CYP3A4 interactions may be at risk of clinically relevant COVID-19-drug interactions, highlighting the need for optimizing dosing regimens in this patient group to improve safety and efficacy.

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来源期刊
CiteScore
6.50
自引率
12.80%
发文量
128
审稿时长
3 months
期刊介绍: An important reference for all pharmacology and toxicology departments, DMD is also a valuable resource for medicinal chemists involved in drug design and biochemists with an interest in drug metabolism, expression of drug metabolizing enzymes, and regulation of drug metabolizing enzyme gene expression. Articles provide experimental results from in vitro and in vivo systems that bring you significant and original information on metabolism and disposition of endogenous and exogenous compounds, including pharmacologic agents and environmental chemicals.
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