COMPOSITION
ALKIXEN capsule: Each capsule contains Crizotinib INN 250 mg.
PHARMACOLOGY
Mechanism of Action:
Crizotinib is an inhibitor of receptor tyrosine kinases including ALK,
Hepatocyte Growth Factor Receptor (HGFR, c-Met), ROS1 (c-ros),
and Recepteur d’Origine Nantais (RON). Translocations can affect
the ALK gene resulting in the expression of oncogenic fusion
proteins. The formation of ALK fusion proteins results in activation
and dysregulation of the gene’s expression and signaling which can
contribute to increased cell proliferation and survival in tumors
expressing these proteins. Crizotinib demonstrated concentra-
tion-dependent inhibition of ALK, ROS1, and c-Met phosphorylation
in cell-based assays using tumor cell lines and demonstrated
antitumor activity in mice bearing tumor xenografts that expressed
echinoderm microtubule-associated protein-like 4 (EML4)-or
nucleophosmin (NPM)-ALK fusion proteins or c-Met.
Pharmacokinetic Properties
Following Crizotinib 250 mg twice daily, steady-state was reached
within 15 days and remained stable, with a median accumulation ratio
of 4.8. Steady-state observed minimum concentration (Cmin ) and
AUC increased in a greater than dose-proportional manner over the
dose range of 200 mg to 300 mg twice daily (0.8 to 1.2 times the
approved recommended dosage).
Absorption
A single Crizotinib dose was absorbed with median time to achieve
peak concentration of 4 to 6 hours, and the mean absolute
bioavailability of Crizotinib was 43% (range: 32% to 66%).
Effect of food
A high-fat meal reduced Crizotinib AUC0-INF and maximum observed
plasma concentration (Cmax) by approximately 14%.
Distribution
The geometric mean volume of distribution (Vss) of Crizotinib was
1772L following a single intravenous dose. Protein binding of
Crizotinib is 91% and is independent of drug concentration in vitro.
Crizotinib is a substrate for P-glycoprotein (P-gp) in vitro. The
blood-to-plasma concentration ratio is approximately 1.
Elimination
The mean apparent plasma terminal half-life of Crizotinib was 42 hours
following single doses of Crizotinib in patients. The mean apparent
clearance (CL/F) of Crizotinib was lower at steady-state (60 L/h) after
250 mg twice daily than after a single 250 mg oral dose (100 L/h).
Metabolism
Crizotinib is predominantly metabolized by CYP3A.
Excretion
Following administration of a single oral 250 mg dose of radiolabeled
Crizotinib dose to healthy subjects, 63% (53% as unchanged) of the
administered dose was recovered in feces and 22% (2.3% as
unchanged) in urine.
INDICATIONS AND USAGE
Crizotinib is a kinase inhibitor indicated for the treatment of
• Patients with metastatic non-small cell lung cancer (NSCLC) whose
tumors are anaplastic lymphoma kinase (ALK) or ROS1
• Positive as detected by an FDA-approved test. Pediatric patients 1
year of age and older and young adults with relapsed or refractory,
systemic anaplastic large cell lymphoma (ALCL) that is ALK-positive
• Limitations of Use: The safety and efficacy of Crizotinib have not
been established in older adults with relapsed or refractory systemic
ALK-positive ALCL.