Phase 1 study to evaluate the effect of the MEK inhibitor trametinib on cardiac repolarization in patients with solid tumours
Phase 1 study to evaluate the effect of the MEK inhibitor trametinib on cardiac repolarization in patients with solid tumours
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DOI：
10.1007/s00280-016-3090-y
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发表时间：
2016-09-01
影响因子：
3
通讯作者：
Sharma, Sunil
中科院分区：
文献类型：
--
作者：
Patnaik, Amita;Tolcher, Anthony;Sharma, Sunil
曲美替尼是一种可逆的选择性丝裂原激活的细胞外信号调节激酶1 （MEK1）和2 （MEK2）抑制剂。与曲美替尼相关的心脏毒性（充血性心力衰竭、心率降低、左心室功能障碍和高血压）是一种罕见但严重的不良事件（AE）。QT间期的延长会增加危及生命的心律失常的风险。因此，我们评估了假定超治疗暴露时曲美替尼诱导QT间期延长的风险。符合条件的实体肿瘤患者在第1天接受安慰剂治疗，第2-14天每天一次曲美替尼2毫克剂量，第15天单次曲美替尼3毫克剂量，以实现QTc测量的超治疗剂量。在给药前、第1天和第15天采用12导联动态心电图监测24小时动态心电图。测定药代动力学（PK）和药效学（PD）参数。35名患者中有32人完成了这项研究。与时间匹配的安慰剂相比，曲美替尼对QTcF、QTcB或QTcI间期的基线变化没有影响。曲美替尼2 mg重复给药后的平均AUC（0 ~ 24）和C（max）分别为364 ng.h/mL和22.9 ng/mL；3mg剂量对应值分别为454 ng.h/mL和29.2 ng/mL。两种剂量的中位时间（max）约为2小时。统计分析和PK/PD模型显示QTcF间隔与曲美替尼血药浓度无显著关系。ae与之前报道的一致。无心电图异常报告为ae。本研究结果表明，曲美替尼对超治疗暴露时QT间期延长无显著影响。
Trametinib is a reversible, selective inhibitor of the mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and 2 (MEK2). Cardiotoxicity (congestive heart failure, decreased heart rate, left ventricular dysfunction, and hypertension) related to trametinib is an infrequent, but serious, adverse event (AE). Prolongation of the QT interval increases the risk of life-threatening cardiac arrhythmia. Thus, the risk of trametinib inducing QT prolongation at putative supratherapeutic exposure was evaluated.Eligible patients with solid tumours received placebo on day 1, once-daily trametinib 2-mg doses on days 2-14, and a single trametinib 3-mg dose on day 15 to achieve supratherapeutic dosing for QTc measurement. Electrocardiogram was assessed by 12-lead ambulatory 24-h Holter monitoring pre-dose, and on day 1 and day 15. Pharmacokinetic (PK) and pharmacodynamics (PD) parameters were measured.Thirty-two of 35 patients completed the study. There was no effect of trametinib when compared with time-matched placebo on the change from baseline in QTcF, QTcB, or QTcI interval. Mean AUC(0-24) and C (max) following trametinib 2-mg repeat doses were 364 ng.h/mL and 22.9 ng/mL, respectively; the corresponding values for the 3-mg dose were 454 ng.h/mL and 29.2 ng/mL. Median T (max) was approximately 2 h for both doses. Statistical analysis and PK/PD modelling showed no significant relationship between QTcF interval and trametinib plasma concentrations. AEs were consistent with those reported previously. No electrocardiogram abnormalities were reported as AEs.The results of this study suggest trametinib has no significant effect on QT prolongation at supratherapeutic exposure.