Indications
Crizotinib is a kinase inhibitor. It is used to treat patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive. Crizotinib is also used for metastatic NSCLC whose tumors are ROS1-positive.
⚠️ Always consult a registered physician before taking any medicine.
Pharmacology
Crizotinib inhibits several 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 and lead to oncogenic fusion proteins. When ALK fusion proteins form, the gene's expression and signaling are activated and dysregulated, which can add to increased cell proliferation and survival in tumors that express these proteins. Cell-based assays using tumor cell lines showed concentration-dependent inhibition of ALK, ROS1 and c-Met phosphorylation. The drug also showed 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.
Absorption
After a single oral dose, crizotinib was absorbed with a median time to peak concentration of 4 to 6 hours. With 250 mg twice daily, steady state was reached within 15 days and stayed stable, with a median accumulation ratio of 4.8. Steady state systemic exposure (C.min and AUC) appeared to rise more than in proportion to the dose across the range of 200 to 300 mg twice daily. Mean absolute bioavailability was 43% (range: 32% to 66%) after a single 250 mg oral dose. A high-fat meal reduced AUCinf and Cmax by approximately 14%.
Distribution
The geometric mean volume of distribution (Vss) was 1772 L after an intravenous 50 mg dose, which points to extensive distribution from the plasma into tissues. Binding to human plasma proteins in vitro is 91% and doesn't depend on drug concentration. Studies done in vitro also suggested that crizotinib is a substrate for P-glycoprotein (P-gp). The blood-to-plasma concentration ratio is approximately 1.
Metabolism
Crizotinib is mainly metabolized by CYP3A4/5, according to in vitro studies. The primary metabolic pathways in humans were oxidation of the piperidine ring to crizotinib lactam and O-dealkylation, followed by Phase 2 conjugation of the O-dealkylated metabolites.
Elimination
Following single doses, the mean apparent plasma terminal half-life was 42 hours in patients. Healthy subjects were given a single 250 mg radiolabeled dose, and 63% of it was recovered in feces and 22% in urine. Unchanged crizotinib made up approximately 53% of the dose in feces and 2.3% in urine. The mean apparent clearance (CL/F) was lower at steady state (60 L/hr) after 250 mg twice daily than after a single 250 mg oral dose (100 L/hr). This was likely due to auto inhibition of CYP3A by crizotinib after multiple dosing.
Pregnancy & Breastfeeding
Crizotinib can harm an unborn baby, going by how the medicine works in the body. There are no data on its use during pregnancy. Women who could become pregnant should be told about the possible risk to a baby and should use effective contraception.
It isn't known whether Crizotinib passes into human milk, what it does to a breastfed infant, or whether it affects milk production. Because breastfed infants could have adverse reactions, patients should not breastfeed during treatment with Crizotinib and for 45 days after the final dose.
⚠️ Talk to your doctor before taking any medicine during pregnancy or while breastfeeding.
Dosage Reference
⚠️ Reference ranges from official sources only. Consult your doctor for personalized dosing.
Side Effects & Interactions
Side Effects
No side-effect data recorded yet.