Crizotinib

Crizotinib is an antineoplastic agent belonging to the pharmacological class of tyrosine kinase inhibitors.

The FDA approved Crizotinib for treating metastatic non-small cell lung cancer (NSCLC)in adults, anaplastic large cell lymphoma (ALCL) in children and inflammatory myofibroblastic tumours (IMT) in both adults and pediatric patients.

When administered orally, Crizotinib has a bioavailability of 43%, and undergoes metabolism in the liver by CYP3A4/5 enzymes. Crizotinib is affected by food, and its distribution involves high plasma protein binding (91%) and interaction with P-glycoprotein. Excretion occurs predominantly via faeces (63%) and urine (22%).

The most common side effects of Crizotinib includes nausea, vomiting, oedema (swelling), and diarrhea.

Crizotinib is available in oral capsules and pellets.

The molecule is available in India, the United States, Canada, countries within the European Union, Australia, Japan and South Korea.

Crizotinib is an antineoplastic agent belonging to the pharmacological class of tyrosine kinase inhibitors.

Anaplastic lymphoma kinase (ALK), Recepteur d'Origine Nantais (RON), hepatocyte growth factor receptor (HGFR, c-MET), and ROS1 (c-ros) are the targets of crizotinib. Oncogenic fusion proteins can be expressed as a result of ALK-gene translocations, inhibiting apoptosis and encouraging cell proliferation when activated. ALK-positive tumours are present in a tiny percentage of patients with NSCLC. Increased kinase activity results from ALK fusing with the chimeric protein echinoderm microtubule-associated protein-like 4 (EML4) in most cases. Cristopinib inhibits ALK by preventing ALK from being phosphorylated and causing the protein to adopt an inactive conformation. Ultimately, this reduces tumour survivability and the rate at which cells with this genetic mutation proliferate.

In vitro assays on tumour cell lines demonstrated that crizotinib inhibits ALK, ROS1, and c-Met phosphorylation in a concentration-dependent manner. Research conducted in vivo on mice harbouring tumour xenografts that expressed c-Met, nucleophosmin (NPM)-ALK fusion proteins, or EML4- demonstrated crizotinib's antitumor activity.

Crizotinib is available in oral capsules and pellets.

Capsules: To be swallowed whole with water/liquid. Do not chew, crush or break it.

Oral pellets: Open the capsule(s) and carefully pour or spoon all the pellets directly into the mouth; do not swallow the capsule(s) whole or chew or crush the pellets before swallowing.

The physician recommends taking this medication orally twice daily, with or without food.

The safety and efficacy is not established in adults with relapsed or refractory, systemic ALK-positive ALCL

Orally: Crizotinib is available in capsule and oral pellet forms and is administered orally. It can be taken with or without food. The capsules should be swallowed whole, not crushed, chewed, or opened. In the case of a missed dose, patients should skip the missed dose and resume the regular dosing schedule. The oral pellets are intended to be sprinkled on a teaspoon of applesauce and swallowed immediately without chewing, followed by a glass of water. Caution is advised for pregnant or breastfeeding individuals.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Crizotinib is available in oral capsules and pellets.

250 mg PO BID

Continue until the disease worsens or the toxicity becomes intolerable.

250 mg PO BID

Continue until the disease worsens or the toxicity becomes unacceptable.

Lowering the dosage

200 mg PO BID is the first dose reduction.

250 mg PO qDay as the second dosage reduction. If an individual cannot take 250 mg PO daily, permanently stop.

Patients can actively manage side effects by altering their diet while receiving Crizotinib treatment. Include foods high in nutrients, such as citrus fruits, berries, cocoa, tomatoes, carrots, sweet potatoes, broccoli, and green leafy vegetables. Choose lean proteins like chicken, meat, and fish. Make staying hydrated a priority by drinking lots of water, herbal tea, and fruit and vegetable juices. Refraining from alcohol and tobacco is crucial for overall well-being. Avoiding processed and refined foods is recommended to promote a health-conscious approach to side effect management.

The dietary restriction should be individualized as per patient requirements.

The adverse reactions related to Crizotinib can be categorized as:

Increased blood creatine phosphokinase

The clinically relevant drug interactions of Crizotinib are briefly summarized here.

The common side effects of Crizotinib include:

Nausea

Vomiting

Diarrhea

Constipation

Stomach upset

Reduced neutrophil count (white blood cell)

Abdominal pain

Visual impairment

Dizziness

Taste change or Metallic taste

Fatigue

Decreased appetite

Rash

Pregnancy Category D (FDA): Use in cases where no safer medication is available and life is in danger. Positive evidence of prenatal risk in humans.

When given to a pregnant woman, it may harm the fetus due to its mode of action.

Before beginning, confirm with females of reproductive potential whether they are pregnant.

When pregnant rats were given oral medication during organogenesis at exposures comparable to the maximum recommended human dose, the results were fetotoxicity and embryotoxicity.

Potentially fertile females: Use reliable contraception during treatment and for at least 45 days after the last dosage.

Males who have potential reproductive partners who are female: During treatment and for at least 90 days following the last dosage, use condoms.

Reduced fertility in both females and males of reproductive potential may occur based on findings from animal reproductive organs.

It's unclear if these impacts on fertility can be reversed.

There is no information on the presence of drugs in human milk, how they affect breastfed infants, or how they affect the production of milk.

Avoid nursing during treatment and for 45 days following the last dosage.

It is unknown whether crizotinib is safe or effective for younger patients. There is little data available, so clinical trials and the needs of specific patients usually determine how it's used in this population.

Paediatric patients with ALK-positive ALCL or ALK-positive IMT

For pediatric patients with ALCL or IMT, the recommended dosage is the recommended dose of 280 mg/m2 of crizotinib twice daily or until disease progression occurs or the toxicity becomes intolerable. The body surface area (BSA)-based recommended crizotinib starting dose schedule for pediatric patients.

<1 year: Safety and efficacy not established.

<0.38 m2: Dose not established

0.38-0.46 m2: 120 mg PO BID

0.47-0.51 m2: 140 mg PO BID

0.52-0.61 m2: 150 mg PO BID

0.62-0.8 m2: 200 mg PO BID

0.81-0.97 m2: 250 mg PO BID

0.98-1.16 m2: 300 mg PO BID

1.17-1.33 m2: 350 mg PO BID

1.34-1.51 m2: 400 mg PO BID

1.52-1.69 m2: 450 mg PO BID

≥1.7 m2: 500 mg PO BID

Mild (CLcr 60-89 mL/min) to moderate

(CLcr 30-59 mL/min) renal impairment based on a population pharmacokinetic analysis: No starting dose adjustment is needed.

Patients with severe renal impairment (CLcr <30 mL/min) who did not require dialysis had higher exposure to crizotinib: For patients without dialysis who have severe renal impairment, give Crizotinib once daily at a dose of 250 mg.

Mild: Steady-state mean AUC and Cmax decreased by 9% (AST >ULN and TB ≤1x ULN or any AST and TB >1x to ≤1.5x ULN).

Moderate: 200 mg PO BID (any AST and TB >1.5x ULN and ≤3x ULN).

Severe: 250 mg PO qDay (any AST and TB > 3x ULN).

In a phase I study, crizotinib dosages ranging from 50 to 300 mg were administered daily or twice daily to 37 patients with various solid tumour cancers that were resistant to treatment. The following studies focused on patients with advanced ALK-positive disease because two of the patients in this group with non-small cell lung cancer (NSCLC) showed a response to therapy when they had echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) mutations. The 6-month progression-free survival rate for crizotinib users in this patient group was roughly 72%. The two-year overall survival rate for ALK mutation-positive patients treated with crizotinib was higher (54% vs36%) than for ALK mutation-positive patients who were not given crizotinib.

In children and young adults with anaplastic large cell lymphoma (ALCL) or pediatric patients with inflammatory myofibroblastic tumour (IMT), crizotinib use may result in hepatotoxicity, pneumonitis, interstitial lung disease (ILD), QT interval prolongation, bradycardia, severe visual loss, embryo-fetal toxicity, and gastrointestinal toxicity.