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RX & OTC Update

Crizotinib (Xalkori)

New hope with targeted therapy for non-small cell lung cancer.

Crizotinib (Xalkori) at a glance


  • Locally advanced or metastatic NSCLC patients who are positive for ALK biomarker
  • Targeted therapy inhibits specific molecules involved in the genesis of tumors.


  • Drug dosing has not been studied in individuals with severe liver or kidney dysfunction
  • Two serious effects have been observed - hepatic toxicity and pneumonitis

Crizotinib (Xalkori) is a tyrosine kinase inhibitor available as an oral capsule that is indicated for treatment of advanced or metastatic non-small cell lung cancer (NSCLC). It is a targeted therapy because it inhibits specific molecules involved in the genesis of tumors.

When cancer develops, the anaplastic lymphoma kinase (ALK) pathway becomes an aberrant signaling pathway that stimulates tumor cell proliferation and growth. In individuals with ALK, a genetic biomarker, the overall 6-month response rate to crizotinib in one trial was 57 percent. Plus, the side effects appeared to be tolerable.

Mechanism of Action

Lung cancer is a leading cause of cancer death in the U.S., and the risk of being diagnosed with lung cancer during your lifetime from
ages 20-60 is approximately 7 percent. NSCLC occurs in more than 85 percent of lung cancer based in 2009 data. A 50 percent, 5-year survival is likely if the cancer is limited to a primary tumor, whereas, there is a 3.7 percent, 5-year survival associated with metastatic disease.

NSCLC presents as a mass in the lung tissue but can metastasize to lymph nodes, brain or adrenal glands. A malignant pleural or pericardial effusion may also occur. In the event of recurrent or advanced disease, subsets of patients with NSCLC with adenocarcinoma histology have a specific genetic mutation called anaplastic lymphoma kinase (ALK).

ALK influences drug selection in treating the disease. Overall, the prevalence of the biomarker is relatively small. In individuals with the ALK gene arrangement, crizotinib received FDA approval for treatment of locally advanced or metastatic NSCLC. A mutation causing drug resistance develops with continued use leading to treatment failure.

Dosage, Costs, Pharmacokinetics

Crizotinib is administered as 250 mg by mouth twice a day. The dose was continued for 28-day cycles in a clinical study, then patients were evaluated for response to therapy and side effects.

Patients should be directed to swallow the capsules whole. They should not open the capsules nor dissolve the contents. The drug can be taken with or without food. However, due to a drug-nutrient interaction, patients should avoid eating grapefruit or drinking grapefruit juice. The average wholesale cost for a 30-day supply is approximately $11,500.

Crizotinib oral capsules are absorbed slowly and reach a median time to peak of 4-6 hours. The bioavailability is 43 percent and ranges from 32-66 percent. Steady state is achieved in about 2 weeks (15 days). The drug is extensively bound to plasma proteins. It is metabolized in two-steps. First, it undergoes oxidation by cytochrome P450 3A4/5 and then undergoes conjugation.

Very little drug is found excreted in the urine. The drug dosing has not been studied in individuals with severe liver or kidney dysfunction. Studies in Asians demonstrated that they achieve higher steady-state plasma concentrations than non-Asians.

Drug Interactions & Side Effects

Crizotinib moderately inhibits hepatic cytochrome P450 (CYP) 3A and also P-glycoprotein enzymes and has the potential to increase plasma concentrations of other drugs. Also, crizotinib drug concentrations were elevated when given with ketaconazole, an azole antifungal and CYP inhibitor. Factors that may reduce drug concentrations of crizotinib include administration with CYP 3A inducers and drugs such as proton pump inhibitors, histamine2 blockers, and antacids. Patients did report reflux symptoms as a side effect of crizotinib so management may be challenging.

Two serious effects have been observed and include hepatic toxicity and pneumonitis, a drug-induced inflammatory lung process. Both side effects occur within months of starting crizotinib. Hepatoxicity occurred in < 1 percent of study patients and it is recommended that liver enzymes (ALT, AST, Alkaline phosphatase) and total bilirubin should be monitored monthly. Patients presenting with sudden change causing dyspnea or cough may indicate impending pneumonitis, which occurred in 1.6 percent of study patients. Diagnostic tests should be performed to differentiate pneumonitis versus lung cancer progression or infection.

The drug also prolongs the QT interval on the electrocardiogram, therefore, monitoring patients with cardiac arrhythmias or taking cardiac-acting drugs is necessary. Peripheral edema was also reported. Due to pharmacokinetic differences in Asians, special care should be taken to detect any potential for added toxicity.

Side effects resulting in drug discontinuation occurred in 3-6 percent of patients. Common gastrointestinal side effects were nausea, vomiting, diarrhea, and constipation. However, vision changes were reported such as double-vision and blurred vision; patients should be cautioned to avoid driving motor vehicles if vision is affected. A complete blood count should be ordered to detect bone marrow suppression, especially neutropenia.

References for this article can be accessed here

Grace Earl is an Ambulatory Care Pharmacist at the University of the Sciences and her practice site is at Hahnemann University Hospital, Philadelphia.

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