Crizotinib
Mechanism :
Crizotinib inhibits multiple receptor tyrosine kinases including anaplastic lymphoma kinase (ALK), ROS1, Hepatocyte Growth Factor Receptor (HGFR), and RON which are involved in tumour proliferation. Thus, by inhibiting these tyrosine kinases Crizotinib inhibits cell proliferation and survival in tumours.
Indication :
- Anaplastic Large Cell Lymphoma: For relapse or refractory ALCL that is ALK+.
Contraindications :
• Hypersensitivity to the drug or its components
• Congenital long QT syndrome
• Creatinine clearance <30 ml/min/BSA
• Caution in:
-QT prolongation
-Torsades de pointes
-Ventricular arrythmia
-Bradycardia
-Congestive heart failure
-Electrolyte abnormalities
-Bilirubin > 1.5 times the upper limit of normal range
Dosing :
Available as capsules of 200 mg, 250 mg.
Dosage according to the body surface area is as follows:
<0.6 m2: Dose not established.
0.6-0.8 m2: 200 mg PO BID.
0.81-1.16 m2: 250 mg PO BID.
1.17-1.51 m2: 400 mg PO BID.
1.52-1.69 m2: 450 mg PO BID.
≥1.70 m2: 400 mg PO BID.
Reduce the dose over time as follows:
First dose reduction:
0.6-0.8 m2: 250 mg PO qDay.
0.81-1.16 m2: 200 mg PO BID
1.17-1.69 m2: 250 mg PO BID.
≥1.70 m2: 400 mg PO BID.
Second dose reduction:
0.6-0.8 m2: Permanently discontinue.
0.81-1.16 m2: 250 mg PO qDay.
1.17-1.69 m2: 200 mg PO BID.
≥1.70 m2: 250 mg PO BID.
Unable to tolerate after 2 dose reductions: Permanently discontinue.
Monitor the following parameters during treatment:
CBC with differential WBC count: Monthly.
Ophthalmic examination: Baseline examination before intiating, follow up including retinal examination within 1 month, followed by every 3 months thereafter.
Liver function test: During the first 2 months of treatment every 2 weeks followed by monthly thereafter.
Adverse Effect :
Serious Reactions
• Hepatotoxicity
• Vision disorder
• Neutropenia
• Lymphopenia
• Thrombocytopenia
• Upper respiratory tract infection
• Interstitial lung disease
• Hypokalaemia
• Bradycardia
• Hypophostaemia
Common reactions
• Headache
• Dyspepsia
• Rash
• Decreased appetite
• Diarrhoea, Nausea, Vomiting
• Oedema
• Constipation
• Dysgeusia
• Pyrexia
Interaction :
Crizotinib is a CYP3A4 substrate and inhibitor thus any drug which involves the CYP3A4 enzyme in its metabolism should not be administered concurrently with Crizotinib.
It is also an OCT2 substrate and OCT2 inhibitor.
Contraindicated:
• Do not co-administer with the following drugs due to risk of QT prolongation and arrythmia:
o Cisapride
o Dronedarone
o Levoketoconazole
o Pimozide
• Posaconazole
o Saquinavir
o Thioridazine
o Lonafarnib
• Crizotinib will increase the levels of the following drugs due to its effect on CYP3A4 metabolism and thereby it increases the risk of their toxicity:
o Flibanserin
o Lomitapide
o Lonafarnib
o Lefamulin
Hepatic Dose :
1. Moderate i.e. AST and Total Bilirubin >1.5 times the upper limit and <3 times the upper limit of the normal range: First dose reduction
2. Severe i.e. AST and Total Bilirubin >3 times the upper limit: Second dose reduction
First dose reduction
• 0.6-0.8 m2: 250 mg PO qDay
• 0.81-1.16 m2: 200 mg PO BID
• 1.17-1.69 m2: 250 mg PO BID
• =1.70 m2: 400 mg PO BID
Second dose reduction
• 0.6-0.8 m2: Permanently discontinue
• 0.81-1.16 m2: 250 mg PO qDay
• 1.17-1.69 m2: 200 mg PO BID
• =1.70 m2: 250 mg PO BID