Mechanisms of gefitinib-induced QT prolongation

Jie, Ling‐Jun; Li, Yun-Da; Zhang, He-Qiang; Liang, Mingzhu; Xie, Huabin; Zhou, Faguang; Zhou, Tian-Li; Xie, Dong; Lin, Jianzhong; Li, Guiyang; Cai, Binni; Zhang, Yanhui; Wang, Yan

doi:10.1016/j.ejphar.2021.174441

Cited by 9 publications

(4 citation statements)

References 38 publications

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“…Also, using whole-cell patch-clamp technique in guinea pig ventricular myocytes, Jie et al. reported that gefitinib could delay repolarization as well as prolong QTc interval by potently blocking hERG channel ( 28 ). Likewise, using a small animal model and primary cardiomyocytes, we previously showed that TKIs suppress the amplitude of the slowly activating delayed-rectifier K + current (IK S ) in a time- and concentration-dependent manner, which could be an important mechanism underlying changes in QTc intervals ( 24 ).…”

Section: Discussionmentioning

confidence: 99%

The association between tyrosine kinase inhibitors and fatal arrhythmia in patients with non-small cell lung cancer in Taiwan

et al. 2023

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ObjectiveAs a standard therapy, tyrosine kinase inhibitors (TKIs) improved survival in patients with non-small cell lung cancer (NSCLC) and epidermal growth factor receptor (EGFR) mutation. However, treatment-related cardiotoxicity, particularly arrhythmia, cannot be ignored. With the prevalence of EGFR mutations in Asian populations, the risk of arrhythmia among patients with NSCLC remains unclear.MethodsUsing data from the Taiwanese National Health Insurance Research Database and National Cancer Registry, we identified patients with NSCLC from 2001 to 2014. Using Cox proportional hazards models, we analyzed outcomes of death and arrhythmia, including ventricular arrhythmia (VA), sudden cardiac death (SCD), and atrial fibrillation (AF). The follow-up duration was three years.ResultsIn total, 3876 patients with NSCLC treated with TKIs were matched to 3876 patients treated with platinum analogues. After adjusting for age, sex, comorbidities, and anticancer and cardiovascular therapies, patients receiving TKIs had a significantly lower risk of death (adjusted HR: 0.767; CI: 0.729–0.807, p < 0.001) than those receiving platinum analogues. Given that approximately 80% of the studied population reached the endpoint of mortality, we also adjusted for mortality as a competing risk. Notably, we observed significantly increased risks of both VA (adjusted sHR: 2.328; CI: 1.592–3.404, p < 0.001) and SCD (adjusted sHR: 1.316; CI: 1.041–1.663, p = 0.022) among TKI users compared with platinum analogue users. Conversely, the risk of AF was similar between the two groups. In the subgroup analysis, the increasing risk of VA/SCD persisted regardless of sex and most cardiovascular comorbidities.ConclusionsCollectively, we highlighted a higher risk of VA/SCD in TKI users than in patients receiving platinum analogues. Further research is needed to validate these findings.

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Section: Discussionmentioning

confidence: 99%

The association between tyrosine kinase inhibitors and fatal arrhythmia in patients with non-small cell lung cancer in Taiwan

et al. 2023

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“…27) Gefitinib can block the hERG channel, an important target of druginduced long QT syndrome. Some researchers 28) have demonstrated through animal experiments that gefitinib can block hERG channels in a concentration-dependent manner by combining with the open and closed states, thus significantly prolongating the QTc interval in isolated guinea pig hearts, and it seems to modulate the kinetic properties of hERG channels, namely, accelerating hERG channel inactivation and reducing steady-state channel inactivation. Gefitinib can interact with the hERG channel amino acids S636, S631, F656, and Y652 to mutate these amino acids, thereby altering the stereoselectivity of gefitinib inhibition.…”

Section: Discussionmentioning

confidence: 99%

Gefitinib Increases the Incidence of QT Prolongation in Patients with Non-Small Cell Lung Cancer

et al. 2023

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Gefitinib (GEF) may increase the risk of corrected QT prolongation (QTc). We aimed to evaluate whether gefitinib increases the risk of corrected QT interval (QTc) prolongation and analyze the associated risk factors.A total of 122 cases of advanced EGFR-mutated non-small cell lung cancer (NSCLC) who received gefitinib therapy from January 2015 to December 2020 were evaluated. The results of at least two resting 12-lead electrocardiogram before and after gefitinib treatment were obtained. The Bazett and Fridericia formulas were used to calculate the QTc interval, and the changes of QTc interval values before and after treatment were evaluated. The correlation between gefitinib and QTc interval prolongation and related risk factors were analyzed.After gefitinib-targeted therapy, 23 patients (18.9%) had a prolonged QTc interval, which increased from a mean of 446 ± 25 ms at baseline to 478 ± 18 ms (P < 0.001). Three of the patients met criteria for Grade 3 QTc prolongation in the common term V5.0 for clinical adverse events. Univariate analysis showed that age (ORR, 1.054; 95% confidence interval [CI], 1.003-1.107; P = 0.038), history of hypertension (ORR, 3.409; 95% CI,; P = 0.01), CCB medication history (ORR, 0.259; 95% CI, 0.094-0.712; P = 0.009), history of lung cancer surgery (ORR, 0.231; 95% CI, 0.064-0.829; P = 0.025), and baseline QT interval (ORR, 0.978; 95% CI, 0.964-0.993; P = 0.004) were important predictors of QTc interval prolongation in patients treated with gefitinib. The results of multivariate analysis showed that the history of lung cancer surgery and the baseline QT interval were important factors affecting QTc interval prolongation in patients treated with gefitinib.Gefitinib increases the risk of QTc prolongation in NSCLC patients, which may be more pronounced in patients with advanced age, hypertension, CCB therapy, lung cancer surgery, and a long QT interval at baseline.

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“…In addition, recurrent myocardial infarction was reported in a patient treated with gefitinib for metastatic carcinoid tumor ( Lynch et al, 2011 ). Thereafter, in-vitro and in-vivo studies were conducted to understand the mechanisms underlying gefitinib-induced QT prolongation and cardiotoxicity ( Korashy et al, 2016 , Jie et al, 2021 ). Studies approved the ability of gefitinib to cause cardiac hypertrophy in cardiomyocyte cell line (H9c2) and Wistar albino rats through induction of oxidative stress and apoptosis ( Zaborowska-Szmit et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Angiotensin II type 1 receptor blockade attenuates gefitinib-induced cardiac hypertrophy via adjusting angiotensin II-mediated oxidative stress and JNK/P38 MAPK pathway in a rat model

Alanazi

Alhamami

Alharbi

et al. 2022

Saudi Pharmaceutical Journal

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Mechanisms of gefitinib-induced QT prolongation

Cited by 9 publications

References 38 publications

The association between tyrosine kinase inhibitors and fatal arrhythmia in patients with non-small cell lung cancer in Taiwan

The association between tyrosine kinase inhibitors and fatal arrhythmia in patients with non-small cell lung cancer in Taiwan

Gefitinib Increases the Incidence of QT Prolongation in Patients with Non-Small Cell Lung Cancer

Angiotensin II type 1 receptor blockade attenuates gefitinib-induced cardiac hypertrophy via adjusting angiotensin II-mediated oxidative stress and JNK/P38 MAPK pathway in a rat model

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