当前位置： SCI文献检索 > CANCER CHEMOTHERAPY AND PHARMACOLOGY期刊下所有文献 > 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.

Abstract：

PURPOSE: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. METHODS: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. RESULTS: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 AUC0-24 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. CONCLUSIONS:The results of this study suggest trametinib has no significant effect on QT prolongation at supratherapeutic exposure.

journal_name

Cancer Chemother Pharmacol

journal_title

Cancer chemotherapy and pharmacology

authors

Patnaik A,Tolcher A,Papadopoulos KP,Beeram M,Rasco D,Werner TL,Bauman JW,Scheuber A,Cox DS,Patel BR,Zhou Y,Hamid M,Schramek D,Sharma S

doi

10.1007/s00280-016-3090-y

subject

Has Abstract

pub_date

2016-09-01 00:00:00

pages

491-500

issue

eissn

0344-5704

issn

1432-0843

pii

10.1007/s00280-016-3090-y

journal_volume

pub_type

杂志文章,多中心研究

在线工具

Phase 1 study to evaluate the effect of the MEK inhibitor trametinib on cardiac repolarization in patients with solid tumours.