Nilotinib

Usage

Nilotinib is prescribed for the treatment of:

• Chronic myeloid leukemia (CML): Specifically, it is used for newly diagnosed chronic phase CML and for chronic phase and accelerated phase CML in adults who are resistant to or intolerant of prior therapy, including imatinib. It is also used in pediatric patients with chronic phase CML with resistance or intolerance to prior therapy, including imatinib.
• Acute lymphoblastic leukemia (ALL): Particularly Philadelphia chromosome-positive ALL.

Pharmacological Classification: Tyrosine kinase inhibitor (TKI).

Mechanism of Action: Nilotinib is a potent inhibitor of Bcr-Abl tyrosine kinase, a protein that plays a key role in the development of CML and Ph+ ALL. By inhibiting this enzyme, nilotinib blocks the growth and spread of cancerous cells, leading to their death (apoptosis). It also inhibits other tyrosine kinases, including c-Kit and PDGFR.

Alternate Names

• International Nonproprietary Name (INN): Nilotinib
• Brand Name: Tasigna

How It Works

Pharmacodynamics: Nilotinib exerts its anti-cancer effect by primarily inhibiting the Bcr-Abl tyrosine kinase, thereby disrupting downstream signaling pathways crucial for cell proliferation and survival. This induces apoptosis (programmed cell death) in Bcr-Abl-expressing cells.

Pharmacokinetics:

• Absorption: Approximately 30% oral bioavailability. Absorption is enhanced when taken with food. A high-fat meal significantly increases absorption.
• Distribution: Widely distributed. High plasma protein binding (98%). Limited information is available on whether it crosses the blood-brain barrier.
• Metabolism: Primarily hepatic metabolism, mainly via CYP3A4. Oxidation and hydroxylation are the main metabolic pathways.
• Elimination: Predominantly eliminated in feces (93%), with 69% as unchanged drug. Negligible renal excretion.

Mode of Action: Nilotinib binds to the ATP-binding site of the Bcr-Abl tyrosine kinase, inhibiting its activity. This prevents the enzyme from phosphorylating its substrates, disrupting downstream signaling pathways that promote cell growth and survival. It is effective against most imatinib-resistant Bcr-Abl mutants, with the exception of T315I.

Receptor Binding/Enzyme Inhibition: Nilotinib is a potent and selective inhibitor of Bcr-Abl tyrosine kinase, c-Kit, and PDGFR.

Elimination Pathways: Primarily eliminated via hepatic metabolism followed by biliary excretion into feces. Negligible renal excretion.

Dosage

Standard Dosage

Adults:

• Newly diagnosed chronic phase CML: 300 mg orally twice daily.
• Chronic or accelerated phase CML resistant/intolerant to prior therapy: 400 mg orally twice daily.
• Administer at least 2 hours after food, then wait 1 hour before eating again.

Children (≥ 1 year):

• Dose is based on body surface area (BSA): 230 mg/m² twice daily, rounded to the nearest 50 mg (maximum single dose: 400 mg).
• Pediatric patients younger than 1 year: Use and dose must be determined by a doctor.

Special Cases:

• Elderly Patients: No specific dose adjustments are required based solely on age.
• Patients with Renal Impairment: No specific dose adjustment is recommended. However, close monitoring is advised.
• Patients with Hepatic Dysfunction: Monitor liver function and consider dose adjustment based on individual patient response and tolerance.
• Patients with Comorbid Conditions: Adjust dose based on the specific comorbidity and its potential impact on drug metabolism and clearance.

Clinical Use Cases

Nilotinib is not typically used in the contexts of intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations like status epilepticus or cardiac arrest. Its primary indication is the treatment of CML and Ph+ ALL.

Dosage Adjustments

Dose adjustments may be necessary based on individual patient response, tolerability, and the presence of drug interactions or specific comorbidities. Monitor for adverse events and adjust the dose accordingly. In case of severe adverse events, consider interrupting treatment until resolution and then resuming at a lower dose.

Side Effects

Common Side Effects:

Rash, itching, headache, nausea, vomiting, fatigue, diarrhea, constipation, abdominal pain, musculoskeletal pain, hair loss, anemia, thrombocytopenia, neutropenia, elevated bilirubin, cough, infections.

Rare but Serious Side Effects:

QT prolongation, pancreatitis, hepatotoxicity, tumor lysis syndrome, fluid retention, cardiovascular events, severe thrombocytopenia, neutropenia, anemia, hemorrhage.

Long-Term Effects:

Chronic complications may include cardiovascular disease, secondary malignancies, and metabolic abnormalities. Long-term monitoring is necessary to assess and manage these potential risks.

Adverse Drug Reactions (ADR):

Any severe or life-threatening adverse event, including those listed above, requires immediate medical attention and possible discontinuation of the drug.

Contraindications

• Long QT syndrome
• Hypokalemia
• Hypomagnesemia
• Hypersensitivity to nilotinib or any of its excipients.

Drug Interactions

Nilotinib interacts with numerous medications. Clinically significant interactions include:

• Strong CYP3A4 inhibitors: Reduce nilotinib dose or avoid concomitant use.
• Strong CYP3A4 inducers: Avoid concomitant use, as they may decrease nilotinib efficacy.
• Proton pump inhibitors (PPIs): Avoid concomitant use. Use H2 blockers or antacids as alternatives, timed appropriately around nilotinib administration.
• Drugs that prolong the QT interval: Avoid concomitant use, including antiarrhythmics (e.g., amiodarone, disopyramide, quinidine) and other drugs known to prolong QT interval.
• Other medications: Numerous other drug interactions exist; consult a comprehensive drug interaction resource before co-prescribing.
• Food: Avoid grapefruit juice and other foods that inhibit CYP3A4.

Pregnancy and Breastfeeding

• Pregnancy: Nilotinib can cause fetal harm. Avoid use during pregnancy unless the potential benefit outweighs the risk. Effective contraception is essential during treatment and for 2 weeks after discontinuation.
• Breastfeeding: Breastfeeding is not recommended during treatment and for 2 weeks after the last dose due to the potential risk to the infant.

Drug Profile Summary

• Mechanism of Action: Bcr-Abl tyrosine kinase inhibitor.
• Side Effects: Rash, itching, headache, nausea, vomiting, fatigue, myelosuppression, QT prolongation, pancreatitis, hepatotoxicity.
• Contraindications: Long QT syndrome, hypokalemia, hypomagnesemia.
• Drug Interactions: CYP3A4 inhibitors/inducers, PPIs, QT-prolonging drugs.
• Pregnancy & Breastfeeding: Avoid.
• Dosage: Adults: 300 mg BID (newly diagnosed CML-CP) or 400 mg BID (resistant/intolerant CML); Children: 230 mg/m² BID.
• Monitoring Parameters: CBC, liver function tests, electrolytes, lipase, lipid profile, QTc interval, blood glucose.

Popular Combinations

While combination therapy is not routinely used with nilotinib in the initial treatment of CML, other agents, such as hydroxyurea or anagrelide, or hematopoietic growth factors (like erythropoietin or G-CSF) may be used concomitantly if clinically indicated.

Precautions

• General Precautions: Monitor for myelosuppression, hepatotoxicity, pancreatitis, QTc prolongation, fluid retention, and cardiovascular events.
• Pregnant Women: Contraindicated unless benefits outweigh risks.
• Breastfeeding Mothers: Avoid.
• Children & Elderly: Monitor closely for adverse events and adjust dosage as needed.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Nilotinib?

A: For newly diagnosed adult CML patients in the chronic phase, it’s 300 mg twice daily. For adults with resistant/intolerant CML in chronic or accelerated phase, it’s 400 mg twice daily. For children, it’s 230 mg/m² twice daily, adjusted based on BSA.

Q2: What are the most common side effects of Nilotinib?

A: Common side effects include rash, itching, headache, nausea, vomiting, fatigue, diarrhea, and musculoskeletal pain.

Q3: What are the serious side effects of Nilotinib?

A: Serious side effects can include QTc prolongation, pancreatitis, hepatotoxicity, and myelosuppression.

Q4: How should Nilotinib be administered?

A: Administer orally, on an empty stomach, at least 2 hours after a meal. Wait at least one hour before eating again after taking the medication.

Q5: What are the contraindications to Nilotinib?

A: Contraindications include long QT syndrome, hypokalemia, and hypomagnesemia.

Q6: What are the key drug interactions with Nilotinib?

A: Important interactions include strong CYP3A4 inhibitors and inducers, proton pump inhibitors (PPIs), and drugs that prolong the QT interval.

Q7: Can Nilotinib be used during pregnancy or breastfeeding?

A: Nilotinib should be avoided during pregnancy and breastfeeding due to the potential for fetal harm and risk to the nursing infant.

Q8: What monitoring is required during Nilotinib therapy?

A: Monitor complete blood counts, liver function, electrolytes, lipase levels, lipid profile, QTc interval, and blood glucose levels regularly.

Q9: How does Nilotinib work?

A: It inhibits the Bcr-Abl tyrosine kinase, which is responsible for the development and progression of CML and Ph+ ALL. This inhibition prevents the uncontrolled growth and division of cancer cells.

Q10: What should patients be advised regarding lifestyle while on Nilotinib?

A: Patients should avoid grapefruit products and other foods that may interfere with drug metabolism. They should also be advised on the importance of adhering to the prescribed dosing schedule and reporting any unusual symptoms to their physician promptly.