ceritinib

ceritinib
IUPAC name	5-Chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine
Tradename	Zykadia
Drugs.com	Monograph
MedlinePlus	a614033
Licence US	Ceritinib
Routes of administration	Oral
CAS number	1032900-25-6
PubChem	57379345
DrugBank	DB09063
ChemSpiderID	34991563
UNII	K418KG2GET
ChEBI	90953
ChEMBL	CHEMBL2007817
Chemical formula	C28H36ClN5O3S
Molecular weight	558.14 g/mol

ceritinib. It is a targeted tyrosine kinase inhibitor used for the treatment of certain non-small cell lung cancer (NSCLC) cases. Specifically, it is indicated for patients whose tumors are anaplastic lymphoma kinase (ALK)-positive, as detected by an approved test. The drug was developed by the pharmaceutical company Novartis and received its initial accelerated approval from the U.S. Food and Drug Administration (FDA) in 2014.

Medical uses

Ceritinib is approved for the treatment of patients with metastatic non-small cell lung cancer whose tumors are positive for the anaplastic lymphoma kinase (ALK) gene rearrangement. This approval by the U.S. Food and Drug Administration and the European Medicines Agency covers use in patients who have progressed on or are intolerant to prior therapy with crizotinib. Clinical trials, such as the ASCEND-1 and ASCEND-4 studies conducted by Novartis, demonstrated its efficacy in this population. The companion diagnostic test for identifying eligible patients is the Ventana ALK (D5F3) CDx Assay.

Adverse effects

Common adverse reactions associated with ceritinib include severe gastrointestinal effects such as diarrhea, nausea, vomiting, and abdominal pain. It can also cause significant elevations in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and blood glucose levels, necessitating regular monitoring. Serious adverse effects include interstitial lung disease/pneumonitis, bradycardia, and QT interval prolongation. The U.S. Food and Drug Administration mandates a Boxed Warning regarding risks of severe gastrointestinal toxicity and hepatotoxicity.

Pharmacology

Ceritinib functions as a potent and selective inhibitor of the anaplastic lymphoma kinase (ALK) tyrosine kinase receptor. It also inhibits insulin-like growth factor 1 receptor (IGF-1R) and ROS1. The drug works by binding to the adenosine triphosphate (ATP)-binding site of the ALK protein, blocking its phosphorylation and subsequent downstream signaling through pathways like the MAPK/ERK pathway and the JAK-STAT signaling pathway. This inhibition leads to reduced proliferation and induced apoptosis in ALK-dependent tumor cells. Its metabolism is primarily hepatic, mediated by the cytochrome P450 enzyme CYP3A4.

Chemistry

Ceritinib is a synthetic small molecule with the chemical name 5-Chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine. It is formulated as the free base and appears as a white to yellowish powder. The compound's structure is based on a diaminopyrimidine core, which is characteristic of many kinase inhibitors developed by companies like Novartis and Pfizer. Its molecular weight is 558.14 g/mol, and it is practically insoluble in aqueous solutions at physiological pH.

History

The development of ceritinib was driven by the need for agents effective against crizotinib-resistant non-small cell lung cancer. Researchers at Novartis identified the compound through extensive screening and optimization efforts. Based on promising results from the phase I ASCEND-1 trial, the U.S. Food and Drug Administration granted it accelerated approval in April 2014 under its Breakthrough Therapy Designation program. Full approval was later secured following the confirmatory phase III ASCEND-4 study. Regulatory endorsements from the European Medicines Agency and other agencies like Health Canada followed.

Society and culture

Ceritinib is marketed globally under the brand name Zykadia by Novartis. Its high cost has been a subject of discussion within healthcare systems, including the National Health Service in the United Kingdom. The drug's approval was a significant milestone for the precision medicine movement in oncology, highlighting the importance of companion diagnostics. Patient access programs have been established by Novartis in various regions. The development of ceritinib and similar agents like alectinib and lorlatinib represents a major advance in the treatment paradigm for ALK-positive lung cancer.

Category:Antineoplastic drugs Category:Tyrosine kinase inhibitors Category:Novartis