Ceritinib

Indications

Ceritinib, a kinase inhibitor, is specifically indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC). It is particularly prescribed for those individuals who have experienced disease progression or exhibit intolerance to crizotinib. This indication has received accelerated approval based on observed tumor response rate and duration of response. It is important to note, however, that an improvement in overall survival or disease-related symptoms has yet to be demonstrated. The continued approval for this indication may depend on the results of confirmatory trials that verify and describe the clinical benefits of ceritinib.

Absorption

Following oral administration, ceritinib reaches peak plasma concentrations within approximately 4 to 6 hours.

Metabolism

Ceritinib undergoes significant metabolic processing primarily via the enzyme CYP3A. In studies conducted in vitro, CYP3A was identified as the major enzyme responsible for the metabolic clearance of ceritinib. After administering a single oral dose of 750 mg of radiolabeled ceritinib, the parent compound was found to be the predominant circulating component in human plasma, comprising about 82% of the observed substances. Understanding the metabolism of ceritinib is crucial for predicting drug interactions and optimizing individual patient dosages based on metabolic capabilities.

Mechanism of Action

Ceritinib functions as a potent inhibitor of Anaplastic Lymphoma Kinase (ALK), also known as the ALK tyrosine kinase receptor or CD246. This enzyme plays a critical role in certain types of cancer due to genetic mutations. Specifically, in approximately 4-5% of non-small cell lung cancers (NSCLCs), a chromosomal rearrangement results in a fusion gene between EML4 (echinoderm microtubule-associated protein-like 4) and ALK. This fusion leads to continuous kinase activity that contributes to cancer development and sustains the malignant characteristics of the cells. Ceritinib's mechanism of action involves the inhibition of ALK autophosphorylation and the phosphorylation of the downstream signaling protein STAT3, thereby suppressing the proliferation of ALK-dependent cancer cells. Additionally, ceritinib has demonstrated efficacy in vitro by inhibiting the proliferation of cell lines expressing EML4-ALK and NPM-ALK fusion proteins. It has also shown dose-dependent inhibition of EML4-ALK-positive NSCLC xenograft growth in both mice and rat models.