Ceritinib

Ceritinib is used for the treatment of adults with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) following failure (secondary to resistance or intolerance) of prior crizotinib therapy. About 4% of patients with NSCLC have a chromosomal rearrangement that generates a fusion gene between EML4 (echinoderm microtubule-associated protein-like 4) and ALK (anaplastic lymphoma kinase), which results in constitutive kinase activity that contributes to carcinogenesis and seems to drive the malignant phenotype. Ceritinib exerts its therapeutic effect by inhibiting autophosphorylation of ALK, ALK-mediated phosphorylation of the downstream signaling protein STAT3, and proliferation of ALK-dependent cancer cells. Following treatment with crizotinib (a first-generation ALK inhibitor), most tumours develop drug resistance due to mutations in key "gatekeeper" residues of the enzyme. This occurrence led to development of novel second-generation ALK inhibitors such as ceritinib to overcome crizotinib resistance. The FDA approved ceritinib in April 2014 due to a surprisingly high response rate (56%) towards crizotinib-resistant tumours and has designated it with orphan drug status.

Ceritinib is an antineoplastic kinase inhibitor used to treat anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) in patients with inadequate clinical response or intolerance to crizotinib.

Ceritinib is a kinase inhibitor indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. This indication is approved under accelerated approval based on tumor response rate and duration of response. An improvement in survival or disease-related symptoms has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

• Refractory
• locally advanced Non-small cell lung cancer
• Refractory
• metastatic Non small cell lung cancer

Ceritinib inhibits Anaplastic lymphoma kinase (ALK) also known as ALK tyrosine kinase receptor or CD246 (cluster of differentiation 246), which is an enzyme that in humans is encoded by the ALK gene. About 4-5% of NSCLCs have a chromosomal rearrangement that generates a fusion gene between EML4 (echinoderm microtubule-associated protein-like 4) and ALK (anaplastic lymphoma kinase), which results in constitutive kinase activity that contributes to carcinogenesis and seems to drive the malignant phenotype. Ceritinib exerts its therapeutic effect by inhibiting autophosphorylation of ALK, ALK-mediated phosphorylation of the downstream signaling protein STAT3, and proliferation of ALK-dependent cancer cells. Ceritinib has been shown to inhibit 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.

After oral administration of ceritinib, peak concentrations were achieved after approximately 4 to 6 hours.

The apparent volume of distribution (Vd/F) is 4230 L following a single 750 mg dose.

Ceritinib is 97% bound to human plasma proteins, independent of drug concentration.

Following oral administration of a single 750 mg radiolabeled ceritinib dose, 92.3% of the administered dose was recovered in the feces (with 68% as unchanged parent compound) while 1.3% of the administered dose was recovered in the urine.

The terminal half life is 41 hours.

The geometric mean apparent clearance (CL/F) of ceritinib was lower at steady-state (33.2 L/h) after 750 mg daily dosing than after a single 750 mg dose (88.5 L/h).

There is not currently any data on carcinogenicity, effect on human fertility, or on early embryonic development. However, based on its mechanism of action, ceritinib may cause fetal harm when administered to pregnant women and should therefore be administered with effective contraception during treatment. Diarrhea, nausea, vomiting, or abdominal pain occurred in 96% of 255 patients including severe cases in 14% of patients. Drug-induced hepatotoxicity also occurred in 27% of 255 patients, presenting as alanine aminotransferase (ALT) levels greater than 5 times the upper limit of normal (ULN). Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis, hyperglycaemia, and bradycardia have also been reported.

• Avoid grapefruit products. Grapefruit inhibits the CYP3A metabolism of ceritinib, which may increase its serum concentration.
• Avoid St. John's Wort. This herb induces the CYP3A metabolism of ceritinib and may reduce its serum concentration.
• Take with food. Food increases the bioavailability of ceritinib. Taking ceritinib in a fasted state increases the risk of adverse gastrointestinal effects like nausea, vomiting, and abdominal pain.