In this article, we will discuss Ceritinib (Mechanism of Action). So, let’s get started.
Mechanism of Action
Ceritinib is a kinase inhibitor. Targets of ceritinib inhibition identified in either biochemical or cellular assays at clinically
relevant concentrations include ALK, insulin-like growth factor 1 receptor (IGF-1R), insulin receptor (InsR), and ROS1.
Among these, ceritinib is most active against ALK. Ceritinib inhibited autophosphorylation of ALK, ALK-mediated phosphorylation of the downstream signaling protein STAT3, and proliferation of ALK-dependent cancer cells in in vitro and in vivo assays.
Ceritinib inhibited the in vitro proliferation of cell lines expressing EML4-ALK and NPM-ALK fusion proteins and demonstrated dose-dependent inhibition of EML4-ALK-positive NSCLC xenograft growth in mice and rats. Ceritinib exhibited dose-dependent anti-tumor activity in mice bearing EML4-ALK-positive NSCLC xenografts with demonstrated resistance to crizotinib, at concentrations within a clinically relevant range.
Twelve of 919 patients (1.3%) treated with Ceritinib 750 mg once daily under fasted conditions with at least one post-baseline ECG assessment were found to have a QTc > 500 msec and 58 patients (6%) had an increase from baseline QTc > 60 msec. In ASCEND-4, a central tendency analysis of the QTc data at average steady-state concentrations demonstrated that the upper bound of the 2-sided 90% CI for QTc was 15.3 msec at Ceritinib 750 mg once daily under fasted conditions. A pharmacokinetic/pharmacodynamic analysis suggested concentration-dependent QTc interval
Ten of 925 patients (1.1%) had bradycardia defined as < 50 beats/minute.