PharmaMar, Avda. De los Reyes, 1, Pol. Ind. La Mina-Norte, Colmenar Viejo, Madrid, 28770, Spain.
Vall d'Hebrón University Hospital and Institute of Oncology (VHIO), 08035, Barcelona, Spain.
Cancer Chemother Pharmacol. 2021 Jan;87(1):113-124. doi: 10.1007/s00280-020-04153-6. Epub 2020 Oct 27.
This study assessed the effect of lurbinectedin, a highly selective inhibitor of oncogenic transcription, on the change from baseline in Fridericia's corrected QT interval (∆QTcF) and electrocardiography (ECG) morphological patterns, and lurbinectedin concentration-∆QTcF (C-∆QTcF) relationship, in patients with advanced solid tumors.
Patients with QTcF ≤ 500 ms, QRS < 110 ms, PR < 200 ms, and normal cardiac conduction and function received lurbinectedin 3.2 mg/m as a 1-h intravenous infusion every 3 weeks. ECGs were collected in triplicate via 12-lead digital recorder in treatment cycle 1 and 2 and analyzed centrally. ECG collection time-matched blood samples were drawn to measure lurbinectedin plasma concentration. No effect on QTc interval was concluded if the upper bound (UB) of the least square (LS) mean two-sided 90% confidence intervals (CI) for ΔQTcF at each time point was < 20 ms. C-∆QTcF was explored using linear mixed-effects analysis.
A total of 1707 ECGs were collected from 39 patients (females, 22; median age, 56 years). The largest UB of the 90% CI of ΔQTcF was 9.6 ms, thus lower than the more conservative 10 ms threshold established at the ICH E14 guideline for QT studies in healthy volunteers. C-∆QTcF was better fit by an effect compartment model, and the 90% CI of predicted ΔQTcF at C was 7.81 ms, also below the 10 ms threshold of clinical concern.
ECG parameters and C-ΔQTcF modelling in this prospective study indicate that lurbinectedin was not associated with a clinically relevant effect on cardiac repolarization.
本研究评估了高度选择性致癌转录抑制剂洛布内丁对晚期实体瘤患者基线 Fridericia 校正 QT 间期（∆QTcF）和心电图（ECG）形态变化的影响，以及洛布内丁浓度-∆QTcF（C-∆QTcF）关系。
QTcF≤500ms、QRS<110ms、PR<200ms、心脏传导和功能正常的患者接受洛布内丁 3.2mg/m2，1 小时静脉输注，每 3 周 1 次。在治疗周期 1 和 2 中，通过 12 导联数字记录仪重复采集 3 次心电图，并进行中心分析。采集时间匹配的 ECG 血样用于测量洛布内丁血浆浓度。如果每个时间点 ∆QTcF 的最小二乘（LS）均值双侧 90%置信区间（CI）的上限（UB）<20ms，则认为 QTc 间期无影响。使用线性混合效应分析来探索 C-∆QTcF。
共采集了 39 例患者（女性 22 例；中位年龄 56 岁）的 1707 份心电图。∆QTcF 90%CI 的最大 UB 为 9.6ms，低于 ICH E14 指南在健康志愿者中 QT 研究中建立的更保守的 10ms 阈值。C-∆QTcF 更适合效应室模型，C 时预测 ∆QTcF 的 90%CI 为 7.81ms，也低于临床关注的 10ms 阈值。
这项前瞻性研究的 ECG 参数和 C-∆QTcF 模型表明，洛布内丁不会对心脏复极产生临床相关影响。
