1) Drug Requested
Ceritinib (Zykadia) Novartis approved April 2014. FDA Rating: chemical type, NME (New Molecular Entity) and given P (priority review) status.1
Requester. John Smith, MD. Division of Hematology and Oncology, Department of Internal Medicine.
2) Pharmacology and Indications:4
Ceritinib is a potent inhibitor of anaplastic lymphoma kinase (ALK), a tyrosine kinase involved in the pathogenesis of nonsmall cell lung cancer (NSCLC). ALK gene abnormalities due to mutations or translocations may result in expression of oncogenic fusion proteins, that alter signaling, and expression and result in increased cellular proliferation and survival in tumors. The primary mechanism of…show more content… AUC and Cmax increased 73% and 41%, respectively when administered with a high-fat meal and 58% and 43%, respectively when taken with a low-fat meal when compared to fasting, which is why is it better taken on an empty stomach to reduce the risk of ADR. Ceritinib is 97% bound to human plasma protein. The volume of distribution following a single oral dose of 750 mg is 4230 L. Metabolism is primarily hepatic via CYP3A. 92% of ingested dose was recovered in the feces (with 68% as unchanged drug) and 1% in urine.
4) Clinical Efficacy:
Clinical trial evaluating the safety and efficacy of ceritinib are limited. PubMed search revealed one published RCT that was phase I and the FDA approval was based on this trial (ASCEND-1 trial by Shaw et al.).
Investigator: Shaw et al. 2014.
Objective: To determine the maximum tolerated dose (MTD), safety, pharmacokinetic properties and antitumor activity of ceritinib in patients with advanced, ALK-rearranged NSCLC and other cancers harboring ALK alterations (n=130).
Design: This was a Phase 1 trial to determine the MTD of ceritinib in adult patients with tumors harboring a genetic alteration in ALK. Secondary objectives were to characterize the safety and side-effect profile, pharmacokinetic profile, and antitumor activity of ceritinib.
Method: Patients with locally advanced or metastatic cancer harboring genetic alterations in ALK were eligible. In patients with NSCLC, the demonstration of ALK rearrangement was required