Gilteritinib

Usage

• Gilteritinib is prescribed for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) harboring an FMS-like tyrosine kinase 3 (FLT3) mutation. Relapsed AML means AML that has returned after treatment. Refractory AML means AML that did not respond to prior treatment. FLT3 mutations are genetic changes to this gene that are frequently implicated in AML.
• Pharmacological Classification: Kinase inhibitor, more specifically a multi-targeted tyrosine kinase inhibitor that targets FLT3.
• Mechanism of Action: Gilteritinib inhibits FLT3, a receptor tyrosine kinase. FLT3 mutations are common drivers in AML, promoting uncontrolled cell growth and proliferation. Gilteritinib inhibits the activity of mutated FLT3, thus suppressing the proliferation and survival of leukemic cells. It also inhibits AXL, a receptor tyrosine kinase associated with acquired resistance to FLT3 inhibitors, thus enhancing the response rate in patients harboring AXL mutations.

Alternate Names

• International Nonproprietary Name (INN): Gilteritinib
• Brand Name: Xospata

How It Works

• Pharmacodynamics: Gilteritinib primarily targets and inhibits FLT3, leading to decreased signaling in leukemic cells, inducing apoptosis (programmed cell death), and inhibiting proliferation. It also inhibits other tyrosine kinases like AXL, which may contribute to its activity.
• Pharmacokinetics:
  • Absorption: Peak plasma concentration is reached 4-6 hours after oral administration. Administering with food may increase Cmax and AUC of the drug.
  • Metabolism: Primarily metabolized in the liver, predominantly by CYP3A4.
  • Elimination: Primarily excreted in the feces (approximately 65%), with a smaller fraction (around 16%) eliminated in the urine as unchanged drug and metabolites. The elimination half-life is approximately 113 hours (almost 5 days).
• Mode of Action: Gilteritinib binds to the ATP-binding pocket of FLT3, inhibiting its tyrosine kinase activity. This blocks downstream signaling pathways crucial for cell proliferation and survival.
• Receptor Binding/Enzyme Inhibition: Inhibits FLT3 and other kinases, including AXL, KIT, PDGFRα/β, and VEGFR2.
• Elimination Pathways: Primarily hepatic metabolism through CYP3A4, followed by fecal excretion. Some renal excretion of unchanged drug and metabolites occurs.

Dosage

Standard Dosage

Adults:

• 120 mg (three 40 mg tablets) orally once daily, with or without food, at approximately the same time each day.
• Do not break, crush, or chew tablets.
• Treatment should continue for at least 6 months or until disease progression or unacceptable toxicity. If no response is observed after 4 weeks, the dose may be increased to 200 mg once daily if tolerated.

Children:

• The safety and efficacy of gilteritinib in children below 18 years of age have not been established.

Special Cases:

• Elderly Patients (≥65 years): No dose adjustment is required.
• Patients with Renal Impairment: No dose adjustment is required.
• Patients with Hepatic Dysfunction: No dose adjustment needed for mild to moderate impairment (Child-Pugh A or B). Gilteritinib is not recommended for severe hepatic impairment (Child-Pugh C).
• Patients with Comorbid Conditions: Caution should be exercised in patients with cardiac conditions, particularly long QT syndrome, or electrolyte imbalances (hypokalemia or hypomagnesemia).

Clinical Use Cases

Gilteritinib’s clinical use is specifically focused on relapsed/refractory FLT3-mutated AML. It’s not indicated for the medical settings described below:

• Intubation: Not applicable.
• Surgical Procedures: Not applicable.
• Mechanical Ventilation: Not applicable.
• Intensive Care Unit (ICU) Use: Not applicable.
• Emergency Situations: Not applicable.

Dosage Adjustments

Dosage adjustments may be necessary due to adverse events (see Table 1 in source [4] and Table 1 in source [21] or Dosage with Toxicity section of source [21]):

• Differentiation Syndrome: Administer systemic corticosteroids and initiate hemodynamic monitoring. Interrupt gilteritinib if severe signs and symptoms persist for more than 48 hours. Resume at previous dose when symptoms improve to Grade ≤2.
• Posterior Reversible Encephalopathy Syndrome (PRES): Discontinue gilteritinib.
• QTc Interval Prolongation:
• If QTcF >500 msec: Interrupt gilteritinib. Resume at 80 mg daily once QTc interval returns to within 30 msec of baseline or is ≤480 msec.
• QTcF interval increase >30 msec on Day 8 of Cycle 1: Confirm with repeat ECG on Day 9. If confirmed, consider dose reduction to 80 mg daily.
• Pancreatitis: Interrupt gilteritinib until resolution. Resume at 80 mg daily.
• Other Grade ≥3 Toxicities: Interrupt until resolution or improvement to Grade 1. Resume at 80 mg daily.
• HSCT: Discontinue one week prior to conditioning. It may be resumed 30 days after if no acute graft-vs-host disease, patient is in CRc and has shown successful engraftment.
• Strong CYP3A, P-gp and/or BCRP Inhibitors: Use with caution and consider dose reduction to 80 mg/day.

Side Effects

Common Side Effects

• Myalgia/arthralgia
• Transaminase elevation
• Fatigue/malaise
• Fever
• Non-infectious diarrhea
• Dyspnea
• Edema
• Rash
• Pneumonia
• Nausea
• Stomatitis
• Cough
• Headache
• Hypotension
• Dizziness
• Vomiting

Rare but Serious Side Effects

• Differentiation syndrome
• Posterior reversible encephalopathy syndrome (PRES)
• QTc interval prolongation
• Pancreatitis
• Severe hepatotoxicity
• Anaphylaxis

Long-Term Effects

Long-term effects are still being studied.

Adverse Drug Reactions (ADR)

• Differentiation syndrome: Requires immediate intervention with corticosteroids and hemodynamic monitoring.
• QTc prolongation: Can lead to serious arrhythmias.
• PRES: Requires discontinuation of gilteritinib and appropriate supportive care.
• Pancreatitis: Warrants drug interruption and management of pancreatitis.
• Anaphylaxis: Requires emergency medical treatment.

Contraindications

• Hypersensitivity to gilteritinib or any of its excipients.

Drug Interactions

• Strong CYP3A Inhibitors (e.g., itraconazole, ketoconazole, clarithromycin): Increase gilteritinib exposure. Avoid concomitant use or closely monitor for adverse effects.
• Strong CYP3A Inducers (e.g., rifampin, phenytoin, carbamazepine): Decrease gilteritinib exposure. Avoid concomitant use.
• P-gp and BCRP inhibitors (e.g., azithromycin, captopril): May increase gilteritinib levels. Co-administer with caution.
• P-gp Inducers: May decrease gilteritinib exposure. Consider alternative treatment for P-gp inducers if possible, otherwise modify dose/frequency of such substrate, and monitor for adverse reactions.
• Substrates of P-gp, BCRP, and OCT1 (e.g., digoxin, rosuvastatin, metformin): Gilteritinib can inhibit these transporters, potentially increasing substrate levels. Caution is advised.
• Drugs that prolong the QT interval (e.g., antiarrhythmics, certain antibiotics): Increase the risk of QTc prolongation with gilteritinib. Avoid concomitant use or monitor closely.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: Gilteritinib can cause fetal harm and is contraindicated during pregnancy. Animal studies have shown teratogenicity and embryo-fetal death.
• Breastfeeding: Gilteritinib is present in rat milk. It is not known if it’s excreted in human milk, but it’s recommended to discontinue breastfeeding during treatment and for 2 months after the last dose.

Drug Profile Summary

• Mechanism of Action: Inhibits FLT3 and AXL tyrosine kinases.
• Side Effects: Common: myalgia/arthralgia, transaminase elevation, fatigue, fever, diarrhea, dyspnea, edema, rash. Serious: differentiation syndrome, QTc prolongation, PRES, pancreatitis.
• Contraindications: Hypersensitivity to gilteritinib.
• Drug Interactions: Strong CYP3A inhibitors/inducers, P-gp and BCRP inhibitors, drugs that prolong QT interval, substrates of P-gp/BCRP/OCT1.
• Pregnancy & Breastfeeding: Contraindicated in pregnancy. Breastfeeding should be discontinued.
• Dosage: Adults: 120 mg orally once daily; Consider 200 mg if tolerated and no response in 4 weeks.
• Monitoring Parameters: Complete blood counts, blood chemistries, ECG (especially for QTc prolongation), signs and symptoms of differentiation syndrome, pancreatitis, and liver dysfunction.

Popular Combinations

Currently limited data exists on common synergistic drug combinations with Gilteritinib outside of a clinical trial setting. It’s use generally involves monotherapy.

Precautions

• General Precautions: Assess blood counts, blood chemistries, and perform ECG prior to treatment and regularly during treatment. Monitor for signs and symptoms of differentiation syndrome, QTc prolongation, pancreatitis, and hepatotoxicity.
• Pregnant Women: Contraindicated.
• Breastfeeding Mothers: Breastfeeding should be discontinued.
• Children & Elderly: Not established for children. No dose adjustment needed for the elderly.
• Lifestyle Considerations: Alcohol consumption, cigarette smoking, and specific food interactions need further investigation. Patients may experience dizziness or syncope. Exercise caution in activities requiring alertness.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Gilteritinib?

A: The recommended starting dose for adults is 120 mg orally once daily. If no response is observed after 4 weeks, the dose can be increased to 200 mg/day if tolerated. No dose adjustment is needed for renal impairment, mild to moderate hepatic impairment, or elderly patients.

Q2: What is the most serious side effect of Gilteritinib?

A: Differentiation syndrome is a serious and potentially fatal side effect. It’s characterized by fever, dyspnea, pulmonary infiltrates, pleural or pericardial effusions and requires prompt treatment with corticosteroids and hemodynamic monitoring. Other serious side effects include QTc interval prolongation, PRES, pancreatitis, severe hepatotoxicity, and anaphylaxis.

Q3: What are the common side effects of Gilteritinib?

A: Common side effects include myalgia/arthralgia, transaminase elevations, fatigue, fever, non-infectious diarrhea, dyspnea, edema, rash, nausea, vomiting, cough, headache, hypotension, and dizziness.

Q4: How does Gilteritinib work?

A: Gilteritinib is a tyrosine kinase inhibitor. It primarily targets FLT3, a receptor tyrosine kinase that plays a key role in AML development and progression, especially when mutated. It also inhibits AXL, a receptor tyrosine kinase implicated in resistance. By inhibiting these kinases, gilteritinib disrupts signaling pathways crucial for cell growth, proliferation, and survival in leukemic cells.

Q5: Can Gilteritinib be used during pregnancy or breastfeeding?

A: No, Gilteritinib is contraindicated during pregnancy due to the risk of fetal harm. Breastfeeding should be discontinued during treatment and for 2 months after the last dose.

Q6: What should be monitored in patients taking Gilteritinib?

A: Patients should be monitored for complete blood counts, blood chemistries, ECG (for QTc interval prolongation), and clinical signs and symptoms of differentiation syndrome, pancreatitis, hepatotoxicity, bleeding, and any other adverse events.

Q7: Are there any drug interactions with Gilteritinib?

A: Yes, Gilteritinib interacts with strong CYP3A inhibitors and inducers, P-gp and BCRP inhibitors, drugs that prolong the QT interval, and substrates of P-gp, BCRP, and OCT1. Close monitoring or dose adjustments may be necessary when co-administering with such drugs.

Q8: What are the contraindications to Gilteritinib?

A: The main contraindication is hypersensitivity to gilteritinib or any of its excipients.

Q9: How is Gilteritinib administered?

A: Gilteritinib is administered orally as tablets, once daily, with or without food. Tablets should be swallowed whole and not crushed, broken, or chewed.

Q10: How long should treatment with Gilteritinib continue?

A: Treatment should continue for at least 6 months or until disease progression or unacceptable toxicity occurs. If no response is seen after 4 weeks and the drug is tolerated, the dose may be increased to 200 mg once daily.