Dasatinib

Usage

• Dasatinib is prescribed for the treatment of:
  • Newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase in adults.
  • Chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML in adults with resistance or intolerance to prior therapy, including imatinib.
  • Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in adults with resistance or intolerance to prior therapy.
  • Ph+ CML in pediatric patients 1 year of age and older.
• Pharmacological Classification: Tyrosine kinase inhibitor (TKI)
• Mechanism of Action: Dasatinib inhibits multiple tyrosine kinases, including BCR-ABL, SRC family kinases (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRβ. This inhibits the proliferation and survival of leukemic cells.

Alternate Names

• International Nonproprietary Name (INN): Dasatinib
• Brand Names: Sprycel, Phyrago

How It Works

• Pharmacodynamics: Dasatinib primarily targets and inhibits the activity of specific tyrosine kinases crucial for the growth and proliferation of certain cancer cells. This leads to decreased cell division and ultimately induces apoptosis (programmed cell death) in these malignant cells.
• Pharmacokinetics:
  • Absorption: Dasatinib is rapidly absorbed after oral administration, with or without food.
  • Metabolism: Primarily metabolized in the liver by CYP3A4.
  • Elimination: Primarily eliminated in the feces; less than 4% is excreted in urine.
• Mode of Action: Dasatinib acts by competitively binding to the ATP-binding site of the target tyrosine kinases. This blocks the phosphorylation activity of these enzymes.
• Receptor Binding/Enzyme Inhibition/Neurotransmitter Modulation: Dasatinib inhibits the activity of BCR-ABL, SRC family kinases (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRβ tyrosine kinases.
• Elimination Pathways: Primarily hepatic metabolism (CYP3A4) followed by fecal excretion. Minor renal excretion.

Dosage

Standard Dosage

Adults:

• Chronic Phase CML: 100 mg orally once daily.
• Accelerated/Blast Crisis CML or Ph+ ALL: 140 mg orally once daily.

Children (1 year and older):

• Dosing is based on body weight:
  • ≥ 45 kg: 100 mg orally once daily.
  • 30 kg to < 45 kg: 70 mg orally once daily.
  • 20 kg to < 30 kg: 60 mg orally once daily.
  • 10 kg to < 20 kg: 40 mg orally once daily.
• Use is not recommended in children younger than 1 year or weighing less than 10 kg.

Special Cases:

• Elderly Patients: No specific dose adjustment is recommended. However, elderly patients may be more sensitive to side effects.
• Patients with Renal Impairment: No dose adjustment is necessary.
• Patients with Hepatic Dysfunction: Dose adjustment is not required, but caution is advised.
• Patients with Comorbid Conditions: Dose adjustments may be necessary depending on the specific comorbid condition.

Clinical Use Cases

Dasatinib is not indicated for use in situations like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations like status epilepticus or cardiac arrest. It’s specifically indicated for the treatment of certain leukemias.

Dosage Adjustments

• Dose interruptions or reductions may be necessary due to myelosuppression, pleural effusion, or other adverse reactions. Dosage adjustments should be made under the guidance of a physician based on the individual patient’s response and tolerability.

Side Effects

Common Side Effects

• Headache, infection, musculoskeletal pain, diarrhea, fatigue, myelosuppression (decreased blood cell counts), cough, dyspnea, rash, pruritus, fluid retention, and hemorrhage.

Rare but Serious Side Effects

• Severe myelosuppression (including febrile neutropenia), severe or fatal bleeding (including CNS hemorrhage), pleural effusion, QT prolongation, congestive heart failure, left ventricular dysfunction, and myocardial infarction.

Long-Term Effects

• Chronic complications from prolonged use can include cardiovascular issues, pulmonary complications, and secondary malignancies.

Adverse Drug Reactions (ADR)

• Severe myelosuppression, severe bleeding, pleural effusion, QT prolongation, and congestive heart failure are serious ADRs requiring immediate intervention.

Contraindications

• Hypersensitivity to dasatinib.
• Concomitant use with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir) unless unavoidable with dose adjustments.
• Coadministration with lefamulin and pimozide.

Drug Interactions

• CYP3A4 Inhibitors: Increase dasatinib levels and risk of toxicity.
• CYP3A4 Inducers: Decrease dasatinib levels and reduce efficacy.
• Gastric Acid Reducing Agents (H2 antagonists, proton pump inhibitors): Decrease dasatinib absorption.
• Drugs that Prolong the QT Interval: Increase risk of QT prolongation.
• Drugs that Cause Bleeding/Bruising (e.g., anticoagulants, antiplatelet agents, NSAIDs): Increase risk of bleeding.
• Grapefruit juice: May increase dasatinib plasma concentrations.
• St. John’s wort: May decrease dasatinib plasma concentrations.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: D
• Fetal Risks: Dasatinib can cause fetal harm, including hydrops fetalis, fetal leukopenia, and fetal thrombocytopenia.
• Breastfeeding: Breastfeeding is not recommended during treatment and for 2 weeks after the last dose due to the potential for serious adverse reactions in nursing infants.

Drug Profile Summary

• Mechanism of Action: Tyrosine kinase inhibitor, targeting BCR-ABL, SRC family kinases, c-KIT, EPHA2, and PDGFRβ.
• Side Effects: Myelosuppression, bleeding, fluid retention, pleural effusion, QT prolongation, cardiovascular events.
• Contraindications: Hypersensitivity, concomitant use with strong CYP3A4 inhibitors or QT prolonging drugs, coadministration with lefamulin and pimozide.
• Drug Interactions: CYP3A4 inhibitors/inducers, gastric acid reducing agents, QT prolonging drugs, drugs that increase bleeding risk.
• Pregnancy & Breastfeeding: Contraindicated in pregnancy, not recommended while breastfeeding.
• Dosage: Adults: 100 mg (CML-CP) or 140 mg (advanced CML/Ph+ ALL) daily. Pediatric dosing based on body weight.
• Monitoring Parameters: Complete blood counts (CBCs), signs and symptoms of bleeding, fluid retention, cardiovascular and pulmonary function.

Popular Combinations

Dasatinib is typically used as a single agent. Combination therapy may be considered in certain cases, but should be carefully evaluated due to the potential for increased toxicity.

Precautions

• General Precautions: Monitor for myelosuppression, bleeding, fluid retention, cardiovascular events, and pulmonary toxicity. Correct hypokalemia or hypomagnesemia before starting treatment.
• Specific Populations:
  • Pregnant Women: Contraindicated.
  • Breastfeeding Mothers: Not recommended.
  • Children & Elderly: Pediatric dosing based on body weight. Elderly patients may be more sensitive to side effects.
• Lifestyle Considerations: Avoid grapefruit juice and St. John’s Wort.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Dasatinib?

A: The standard adult dosage is 100 mg daily for chronic phase CML and 140 mg daily for advanced CML or Ph+ ALL. Pediatric dosing is weight-based.

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

A: Common side effects include myelosuppression, fluid retention, pleural effusion, bleeding, headache, fatigue, diarrhea, rash, and musculoskeletal pain.

Q3: What are the serious side effects of Dasatinib?

A: Severe myelosuppression, bleeding, pleural effusion, QT prolongation, and cardiac events can occur and require urgent medical attention.

Q4: Can Dasatinib be used during pregnancy or breastfeeding?

A: Dasatinib is contraindicated during pregnancy. Breastfeeding is not recommended during treatment.

Q5: What are the major drug interactions with Dasatinib?

A: Strong CYP3A4 inhibitors and inducers, drugs that prolong the QT interval, and drugs that increase bleeding risk can interact with Dasatinib. Avoid grapefruit juice and St. John’s wort.

Q6: How does Dasatinib work?

A: Dasatinib is a tyrosine kinase inhibitor that blocks specific enzymes needed for cancer cell growth and survival.

Q7: What should be monitored in patients taking Dasatinib?

A: Close monitoring of complete blood counts, signs of bleeding and fluid retention, as well as cardiovascular and pulmonary function is essential.

Q8: What are the contraindications to Dasatinib?

A: Hypersensitivity to dasatinib, concomitant use with strong CYP3A4 inhibitors or QT prolonging drugs, coadministration with lefamulin and pimozide.

Q9: What should I do if my patient develops pleural effusion while on Dasatinib?

A: Interrupt Dasatinib treatment until the patient is asymptomatic or has returned to baseline. Consider diuretics or corticosteroids if the effusion does not resolve within a week. Dose reduction may be necessary upon reintroduction of Dasatinib.

Q10: Can Dasatinib be crushed or chewed?

A: No, Dasatinib tablets should be swallowed whole to minimize the risk of dermal exposure.