Department of Pulmonary Medicine, Amsterdam UMC, location AMC, Amsterdam, the Netherlands; Amsterdam Institute for Infection and Immunity, Amsterdam, the Netherlands; Amsterdam Public Health, Amsterdam, the Netherlands.
Department of Pulmonary Medicine, Amsterdam UMC, location VUmc, Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands.
Eur J Pharm Sci. 2023 May 1;184:106418. doi: 10.1016/j.ejps.2023.106418. Epub 2023 Mar 2.
In the randomized double-blind placebo-controlled CounterCOVID study, oral imatinib treatment conferred a positive clinical outcome and a signal for reduced mortality in COVID-19 patients. High concentrations of alpha-1 acid glycoprotein (AAG) were observed in these patients and were associated with increased total imatinib concentrations.
This post-hoc study aimed to compare the difference in exposure following oral imatinib administration in COVID-19 patients to cancer patients and assess assocations between pharmacokinetic (PK) parameters and pharmacodynamic (PD) outcomes of imatinib in COVID-19 patients. We hypothesize that a relatively higher drug exposure of imatinib in severe COVID-19 patients leads to improved pharmacodynamic outcome parameters.
648 total concentration plasma samples obtained from 168 COVID-19 patients were compared to 475 samples of 105 cancer patients, using an AAG-binding model. Total trough concentration at steady state (Ct) and total average area under the concentration-time curve (AUCt) were associated with ratio between partial oxygen pressure and fraction of inspired oxygen (P/F), WHO ordinal scale (WHO-score) and liberation of oxygen supplementation (Olib). Linear regression, linear mixed effects models and time-to-event analysis were adjusted for possible confounders.
AUCt and Ct were respectively 2.21-fold (95%CI 2.07-2.37) and 1.53-fold (95%CI 1.44-1.63) lower for cancer compared to COVID-19 patients. Ct, not AUCt, associated significantly with P/F (β=-19,64; p-value=0.014) and Olib (HR 0.78; p-value= 0.032), after adjusting for sex, age, neutrophil-lymphocyte ratio, dexamethasone concomitant treatment, AAG and baseline P/F-and WHO-score. Ct, but not AUCt associated significantly with WHO-score. These results suggest an inverse relationship between PK-parameters, Ct and AUCt, and PD outcomes.
COVID-19 patients exhibit higher total imatinib exposure compared to cancer patients, attributed to differences in plasma protein concentrations. Higher imatinib exposure in COVID-19 patients did not associate with improved clinical outcomes. Ct and AUCt inversely associated with some PD-outcomes, which may be biased by disease course, variability in metabolic rate and protein binding. Therefore, additional PKPD analyses into unbound imatinib and its main metabolite may better explain exposure-response.
在随机、双盲、安慰剂对照的 CounterCOVID 研究中，口服伊马替尼治疗使 COVID-19 患者的临床结局呈阳性，并显示出降低死亡率的信号。在这些患者中观察到α-1酸性糖蛋白（AAG）浓度升高，并且与总伊马替尼浓度增加相关。
本回顾性研究旨在比较 COVID-19 患者与癌症患者口服伊马替尼后的暴露差异，并评估 COVID-19 患者中伊马替尼的药代动力学（PK）参数与药效学（PD）结果之间的关联。我们假设严重 COVID-19 患者中伊马替尼的相对较高药物暴露会导致药效学结果参数的改善。
使用 AAG 结合模型，比较了 168 例 COVID-19 患者的 648 个总浓度血浆样本和 105 例癌症患者的 475 个样本。稳态时总谷浓度（Ct）和总平均浓度-时间曲线下面积（AUCt）与氧分压与吸入氧分数（P/F）、世界卫生组织（WHO）等级量表（WHO 评分）和氧气补充释放（Olib）的比值相关。线性回归、线性混合效应模型和生存时间分析调整了可能的混杂因素。
与 COVID-19 患者相比，癌症患者的 AUCt 和 Ct 分别低 2.21 倍（95%CI 2.07-2.37）和 1.53 倍（95%CI 1.44-1.63）。在调整性别、年龄、中性粒细胞-淋巴细胞比值、地塞米松伴随治疗、AAG 和基线 P/F-和 WHO 评分后，Ct 而不是 AUCt 与 P/F（β=-19.64；p 值=0.014）和 Olib（HR 0.78；p 值=0.032）显著相关。Ct 但不是 AUCt 与 WHO 评分显著相关。这些结果表明 PK 参数、Ct 和 AUCt 与 PD 结果之间呈负相关。
与癌症患者相比，COVID-19 患者表现出更高的总伊马替尼暴露，这归因于血浆蛋白浓度的差异。COVID-19 患者中更高的伊马替尼暴露与改善的临床结局无关。Ct 和 AUCt 与一些 PD 结果呈负相关，这可能受到疾病过程、代谢率和蛋白结合的变异性的影响。因此，对无结合伊马替尼及其主要代谢物的额外 PKPD 分析可能更好地解释暴露-反应关系。
