Crizotinib

Uses

Crizotinib is a kinase inhibitor used for the treatment of patients with-

• • Metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive
• • Metastatic NSCLC whose tumors are ROS1-positive

Crizotinib is also used to associated treatment for these conditions: Metastatic Non-Small Cell Lung Cancer

How Crizotinib works

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.

Dosage

Crizotinib dosage

Recommended Dose: 250 mg orally, twice daily

• Renal Impairment: 250 mg orally, once daily in patients with severe renal impairment (creatinine clearance <30 mL/min) not requiring dialysis.

Geriatric Use

No differences in safety or efficacy were observed between older and younger patients. Clinical studies of Crizotinib in patients with ROS1-positive metastatic NSCLC did not include sufficient numbers of patients age 65 years and older to determine whether they respond differently from younger patients

Hepatic Impairment

Caution should be used in patients with hepatic impairment

Renal Impairment

No starting dose adjustment is needed for patients with mild (CLcr 60-89 mL/min) or moderate (CLcr 30-59 mL/min) renal impairment based on a population pharmacokinetic analysis.

Increased exposure to crizotinib occurred in patients with severe renal impairment (CLcr <30 mL/min) not requiring dialysis. Crizotinib should be administered at a dose of 250 mg taken orally once daily in patients with severe renal impairment not requiring dialysis.

Pediatric Dose

The safety and effectiveness of Crizotinib in pediatric patients have not been established.

Side Effects

The most common adverse reactions (≥25%) are vision disorders, nausea, diarrhea, vomiting, edema, constipation, elevated transaminases, fatigue, decreased appetite, upper respiratory infection, dizziness, and neuropathy.

Precaution

Hepatotoxicity: Patients should undergo periodic liver testing. Crizotinib should be temporarily suspended, dose reduced or permanently suspended

• Interstitial lung disease (ILD)/ Pneumonitis: Drug should be permanently discontinued in patients with ILD/ Pneumonitis

• QT interval prolongation: Electrocardiograms and electrolytes in patients who have a history of or predisposition for QTc prolongation, or who are taking medications that prolong QT should be monitored. Crizotinib should be temporarily suspended, dose reduced or permanently suspended

• Bradycardia: Crizotinib can cause bradycardia. Heart rate and blood pressure should be regularly monitored. Crizotinib should be temporarily suspended, dose reduced or permanently suspended

• Severe visual loss: Ophthalmological evaluation should be performed. Crizotinib should be discontinued in severe visual loss

• Embryo-fetal toxicity: Crizotinib can cause fetal harm. Females of reproductive potential should be advised of the potential risk to a fetus and use of effective contraception

Interaction

CYP3A Inhibitors: Concurrent use of Crizotinib should be avoided with strong CYP3A inhibitors including but not limited to atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, and voriconazole

CYP3A Inducers: Concurrent use of Crizotinib should be avoided with strong CYP3A inducers including but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and St. John’s Wort

CYP3A Substrates: Concurrent use of Crizotinib should be avoided with CYP3A substrates with narrow therapeutic indices including but not limited to alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus

Food Interaction

• Avoid grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase the serum levels of crizotinib.
• Avoid St. John's Wort. This herb induces CYP3A4 metabolism, which may reduce serum levels of crizotinib.
• Take with or without food. High-fat food decreases drug absorption, but not to a clinically significant extent.

[Major] GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of crizotinib.

The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.

Because crizotinib is associated with concentration-dependent prolongation of the QT interval, increased levels may potentiate the risk of ventricular arrhythmias such as torsade de pointes and sudden death.

Food has no significant effect on the gastrointestinal absorption of crizotinib.

According to the product labeling, a high-fat meal reduced crizotinib peak plasma concentration (Cmax) and systemic exposure (AUC) by approximately 14%.

MANAGEMENT: Patients treated with crizotinib should avoid consumption of grapefruit, grapefruit juice, and any supplement containing grapefruit extract.

Crizotinib may be taken without regards to food.

Crizotinib Drug Interaction

Major: doxorubicin, ondansetron, sertralineModerate: paclitaxel protein-bound, fluticasone / salmeterol, rosuvastatin, glycerin, metoprololMinor: sulfamethoxazole / trimethoprimUnknown: charcoal, pioglitazone, aspirin, lorazepam, ubiquinone, copper gluconate, heparin, esomeprazole, bioflavonoids, acetaminophen, cholecalciferol

Crizotinib Disease Interaction

Major: QT prolongationModerate: bradycardia, gastrointestinal perforation, hepatic impairment, renal impairment, visual loss, lung toxicity

Volume of Distribution

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.

Elimination Route

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.

Half Life

Plasma terminal half-life, patients = 42 hours

Clearance

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.

Elimination Route

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.

Pregnancy & Breastfeeding use

Based on its mechanism of action, Crizotinib can cause fetal harm when administered to a pregnant woman. There are no available data on the use of Crizotinib during pregnancy. Females of reproductive potential should be advised of the potential risk to a fetus and use of effective contraception.

There is no information regarding the presence of Crizotinib in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for adverse reactions in breastfed infants patients should not breastfeed during treatment with Crizotinib and for 45 days after the final dose.

Geriatric Use

No differences in safety or efficacy were observed between older and younger patients. Clinical studies of Crizotinib in patients with ROS1-positive metastatic NSCLC did not include sufficient numbers of patients age 65 years and older to determine whether they respond differently from younger patients

Hepatic Impairment

Caution should be used in patients with hepatic impairment

Renal Impairment

No starting dose adjustment is needed for patients with mild (CLcr 60-89 mL/min) or moderate (CLcr 30-59 mL/min) renal impairment based on a population pharmacokinetic analysis.

Increased exposure to crizotinib occurred in patients with severe renal impairment (CLcr <30 mL/min) not requiring dialysis. Crizotinib should be administered at a dose of 250 mg taken orally once daily in patients with severe renal impairment not requiring dialysis

Interaction with other Medicine

CYP3A Inhibitors: Concurrent use of Crizotinib should be avoided with strong CYP3A inhibitors including but not limited to atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, and voriconazole

CYP3A Inducers: Concurrent use of Crizotinib should be avoided with strong CYP3A inducers including but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and St. John’s Wort

CYP3A Substrates: Concurrent use of Crizotinib should be avoided with CYP3A substrates with narrow therapeutic indices including but not limited to alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus

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