Crizotinib

450.343

450.34

1308068-626-2

53AH36668S

749005

C74061

L01XE16|L - Antineoplastic and immunomodulating agents

29333990

78

3.7

1.5±0.1 g/cm3

192 °C

599.177°C at 760 mmHg

316.2±30.1 °C

1.673

Ⅲ

IRRITANT

3077

3

9

24/25

P273-P280-P305 + P351 + P338

H317-H319-H341-H400

|Danger|H317 (100%): May cause an allergic skin reaction [Warning Sensitization, Skin]|P201, P202, P261, P264, P272, P273, P280, P281, P302+P352, P305+P351+P338, P308+P313, P310, P321, P333+P313, P337+P313, P363, P391, P405, and P501|Aggregated GHS information provided by 72 companies from 5 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

In large early clinical trials, elevations in serum aminotransferase levels occurred in up to 57% of patients treated with standard doses of crizotinib, were greater than 5 times ULN in 6% of patients, and led to early discontinuation of therapy in 2% to 4% of patients. Serum aminotransferase elevations typically arose after 4 to 12 weeks of treatment, but usually without jaundice or alkaline phosphatase elevations. Restarting crizotinib after resolution of the aminotransferase abnormalities can be done starting with a reduced dose. Most cases of liver injury due to crizotinib have been minimally or not symptomatic, and the injury resolved within 1 to 2 months of stopping the drug (Case 1). However, cases with jaundice and symptoms during crizotinib therapy have been reported which were fatal in 0.1% of treated patients (Case 2). The severe cases of liver injury due to crizotinib typically arose within 2 to 6 weeks of starting therapy and presented with marked elevations in serum aminotransferase levels followed by jaundice, progressive hepatic dysfunction, coagulopathy, encephalopathy and death. For these reasons, routine periodic monitoring of liver tests at 2 to 4 week intervals during therapy is recommended.

Crizotinib is 91% bound to plasma protein. This is not affected by drug concentration.

Crizotinib is used for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) that is anaplastic-lymphoma kinase (ALK)-positive as detected by a FDA-approved test.|FDA Label|Xalkori is indicated for the first-line treatment of adults with anaplastic lymphoma kinase (ALK) positive advanced non-small cell lung cancer (NSCLC).Xalkori is indicated for the treatment of adults with previously treated anaplastic lymphoma kinase (ALK) positive advanced non-small cell lung cancer (NSCLC).|Treatment of lung malignant neoplasms|Treatment of anaplastic large cell lymphoma, Treatment of inflammatory myofibroblastic tumours|Drug: Crizotinib

Crizotinib is a selective tyrosine kinase receptor inhibitor used in the therapy of selected cases of advanced non-small cell lung cancer. Crizotinib is associated with transient elevations in serum aminotransferase levels during treatment and rare instances of clinically apparent acute liver injury that can be severe and even fatal.

Antineoplastic Agents

Substances that inhibit or prevent the proliferation of NEOPLASMS. (See all compounds classified as Antineoplastic Agents.)|Agents that inhibit PROTEIN KINASES. (See all compounds classified as Protein Kinase Inhibitors.)

The peak serum concentration was reached in 4 to 6 hours following an oral single-dose administration. Steady state was reached within 15 days when a dose of 250 mg twice daily was administered. The mean absolute bioavailability was 43% (range of 32% to 66%) following a single 250 mg oral dose. When taken with high-fat meal, AUC and Cmax were reduced.|Following the administration of a single 250 mg radiolabeled crizotinib dose to healthy subjects, 63% and 22% of the administered dose was recovered in feces and urine, respectively. Unchanged crizotinib represented approximately 53% and 2.3% of the administered dose in feces and urine, respectively.|Mean volume of distribution (Vss) is 1772 L following intravenous administration of a 50 mg dose. This high volume of distribution suggest extensive distribution into tissue from plasma.|The mean apparent clearance (CL/F) of crizotinib was lower at steady state (60 L/hr) after 250 mg twice daily than that after a single 250 mg oral dose (100 L/hr), which was likely due to autoinhibition of CYP3A by crizotinib after multiple dosing.

Crizotinib is metabolized by CYP3A4 and CYP3A5 in which these enzymes mediates the O-dealkylation of the drug.

Plasma terminal half-life, patients = 42 hours

Crizotinib is a tyrosine kinase receptor inhibitor. More specifically, it inhibits anaplastic lymphoma kinase (ALK), hepatocyte growth factor receptor (HGFR, c-MET), and Recepteur d'Origine Nantais (RON). Abnormalities in the ALK gene caused by mutations or translocations may lead to expression of oncogenic fusion proteins. In patients with NSCLC, they have the EML4-ALK gene. Crizotinib inhibits ALK tyrosine kinase which ultimately results in decreased proliferation of cells that carry the genetic mutation and tumour survivability.

crizotinib

Human drugs -> Xalkori -> EMA Drug Category|Antineoplastic agents -> Human pharmacotherapeutic group|Human Drugs -> EU pediatric investigation plans|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients