Exposure-response analysis of oral and intravenous imatinib in critically ill patients with COVID-19 acute respiratory distress syndrome

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutical Sciences Pub Date : 2025-10-17 DOI:10.1016/j.ejps.2025.107332

M.M. Said , A.M. Braam , E. Duijvelaar , J.R. Schippers , L. Atmowihardjo , J. Twisk , H.J. Bogaard , E.L. Swart , J. Aman , I.H. Bartelink

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引用次数: 0

Abstract

Introduction

Imatinib, initially approved for chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST), was investigated in two randomized placebo-controlled trials for its potential effect on COVID-19-related ARDS (C-ARDS). A known relationship between imatinib concentrations and effectiveness exists in CML and GIST, but this is uncharacterized in critically ill C-ARDS patients, where standard dosing may not be suitable.

Aims

This study aims to explore the association between unbound imatinib, total imatinib, and total N-desmethyl-imatinib exposure with clinical outcomes in critically ill C-ARDS patients.

Methods

This post-hoc analysis included C-ARDS patients from the CounterCOVID and InventCOVID trials, all requiring invasive ventilation. In the CounterCOVID trial, patients received 800 mg imatinib on day 1, followed by 400 mg once daily for 9 days. In InventCOVID, the dose was 200 mg intravenously twice daily for 7 days or until ICU discharge. A pharmacokinetic (PK) model simulated the concentration-time profiles of total imatinib (T), unbound imatinib (U), and the sum of total imatinib plus its metabolite desmethyl-imatinib (PM). PK samples were used to estimate individual PK parameters, after which associations with clinical outcomes (WHO score, P/F ratio, ICU stay, ventilator-free days, and mortality) were tested using linear mixed models and regression analysis.

Results

Data from 53 patients revealed that critically ill patients reached higher total imatinib exposure but similar unbound imatinib exposure compared to others. Critical illness and concurrent treatments influenced imatinib exposure. No clear exposure-response relationship was found between imatinib exposure and clinical outcomes.

Conclusion

Although critical illness was linked to higher imatinib exposure, no exposure-response relationship was found. Disease severity may have also impacted the drug’s effectiveness, suggesting that ICU patients may require adjusted dosing. Future clinical studies of repurposed drugs should focus on exposure-response relationships to better understand optimal dosing in new patient populations, particularly for highly protein-bound drugs.

Trial Registration

ClinicalTrials.gov Identifier: NCT04794088, registered 11 March 2021. European Clinical Trials Database (EudraCT number: 2020-005447-23).

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重症COVID-19急性呼吸窘迫综合征患者口服和静脉注射伊马替尼的暴露反应分析

伊马替尼最初被批准用于慢性髓性白血病（CML）和胃肠道间质瘤（GIST），在两项随机安慰剂对照试验中研究了其对covid -19相关ARDS （C-ARDS）的潜在影响。已知在CML和GIST中存在伊马替尼浓度与有效性之间的关系，但在危重C-ARDS患者中没有这种特征，标准剂量可能不适合。目的：本研究旨在探讨未结合伊马替尼、总伊马替尼和总n -去甲基伊马替尼暴露与危重C-ARDS患者临床结局的关系。方法：该事后分析包括来自CounterCOVID和InventCOVID试验的C-ARDS患者，均需要有创通气。在CounterCOVID试验中，患者在第1天接受800毫克伊马替尼，随后每天一次400毫克，持续9天。在InventCOVID中，剂量为200mg静脉滴注，每天两次，持续7天或直到ICU出院。药代动力学（PK）模型模拟了总伊马替尼(T)、未结合伊马替尼(U)和总伊马替尼及其代谢物去甲基伊马替尼（PM）的浓度-时间分布。使用PK样本估计个体PK参数，然后使用线性混合模型和回归分析检验与临床结果（WHO评分、P/F比、ICU住院时间、无呼吸机天数和死亡率）的相关性。结果：来自53例患者的数据显示，危重患者的伊马替尼总暴露量较高，但与其他患者相比，非结合伊马替尼暴露量相似。危重疾病和同期治疗影响伊马替尼暴露。伊马替尼暴露与临床结果之间没有明确的暴露-反应关系。结论：虽然危重疾病与较高的伊马替尼暴露有关，但没有发现暴露-反应关系。疾病的严重程度也可能影响药物的有效性，这表明ICU患者可能需要调整剂量。未来对重新利用药物的临床研究应侧重于暴露-反应关系，以更好地了解新患者群体的最佳剂量，特别是对高蛋白结合药物。试验注册：ClinicalTrials.gov标识符：NCT04794088，注册于2021年3月11日。欧洲临床试验数据库（edraft number: 2020-005447-23）。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

European Journal of Pharmaceutical Sciences 医学-药学

CiteScore

9.60

自引率

2.20%

发文量

248

审稿时长

50 days

期刊介绍： The journal publishes research articles, review articles and scientific commentaries on all aspects of the pharmaceutical sciences with emphasis on conceptual novelty and scientific quality. The Editors welcome articles in this multidisciplinary field, with a focus on topics relevant for drug discovery and development. More specifically, the Journal publishes reports on medicinal chemistry, pharmacology, drug absorption and metabolism, pharmacokinetics and pharmacodynamics, pharmaceutical and biomedical analysis, drug delivery (including gene delivery), drug targeting, pharmaceutical technology, pharmaceutical biotechnology and clinical drug evaluation. The journal will typically not give priority to manuscripts focusing primarily on organic synthesis, natural products, adaptation of analytical approaches, or discussions pertaining to drug policy making. Scientific commentaries and review articles are generally by invitation only or by consent of the Editors. Proceedings of scientific meetings may be published as special issues or supplements to the Journal.