Dasatinib

Dasatinib is an oral tyrosine kinase inhibitor (TKI) used primarily in the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia. It was developed to target the BCR-ABL fusion protein, which results from the Philadelphia chromosome abnormality a hallmark of these leukemias. Approved by the U.S. FDA in 2006, dasatinib is marketed under the brand name Sprycel. It is effective in both newly diagnosed and imatinib-resistant or -intolerant cases. Dasatinib also inhibits other kinases, including SRC family kinases, which may contribute to its broader anti-leukemic activity.

BRAND NAMES

Sprycel: This is the most commonly recognized brand name for Dasatinib. It is used primarily to treat CML and Philadelphia chromosome-positive ALL in both adults and children.

MECHANISM OF ACTION

Dasatinib binds to the ATP-binding site of the BCR-ABL fusion protein, which results from the Philadelphia chromosome translocation in CML and Ph+ ALL, inhibiting abnormal cell division and survival. Additionally, it blocks SRC family kinases, which are involved in cell adhesion, migration, and survival, enhancing its anti-tumor effects. Dasatinib also targets other kinases, including c-KIT, which regulates stem cell growth, and PDGFR, contributing to its broader anti-cancer activity.

PHAMACOKINETICS

Absorption:

Rapidly absorbed with peak plasma concentration in 1–2 hours. Bioavailability is Low (15%) due to extensive first-pass metabolism.

Distribution:

Widely distributed, 96% protein-bound to plasma proteins

Metabolism:

Primarily metabolized in the liver by CYP3A4

Excretion:

Mainly excreted in feces, with a small amount in urine and half-life approximately 3–5 hours

DOSAGE AND ADMINISTRATION

Dasatinib is typically dosed as 100 mg once daily for chronic myelogenous leukemia (CML) - Philadelphia chromosome positive (Ph+), and 140 mg once daily for acute lymphoblastic leukemia (Ph+ ALL), with the maintenance dose continuing at the same daily amount, adjusted based on response and tolerance. It should be taken orally, with or without food, and the tablet must be swallowed whole with water, not crushed or chewed. Dose adjustments may be necessary based on side effects, blood counts, or treatment response, with reductions or interruptions needed in cases of severe adverse effects like neutropenia or thrombocytopenia

DRUG INTERACTIONS

CYP3A4 Inhibitors (e.g., ketoconazole) – can increase dasatinib levels, raising toxicity risk.
CYP3A4 Inducers (e.g., rifampin) – can decrease dasatinib effectiveness.
Anticoagulants/Antiplatelets – increased bleeding risk.
Proton Pump Inhibitors (e.g., omeprazole) – may alter absorption.
H2-Receptor Antagonists/Antacids – may reduce dasatinib effectiveness; take 2 hours apart.
Other Chemotherapy Agents – increases risk of myelosuppression.

CONTRAINDICATIONS

Hypersensitivity: Known allergy to dasatinib or any of its components.
Severe Liver Impairment: Patients with severe hepatic dysfunction should avoid dasatinib due to potential accumulation and increased risk of side effects.
Severe Pulmonary Arterial Hypertension (PAH): Patients with severe PAH should not use dasatinib due to an increased risk of worsening symptoms.

SIDE EFFECTS

Hematologic: Neutropenia, thrombocytopenia, anemia
Cardiovascular: Fluid retention, hypertension, pulmonary arterial hypertension
Gastrointestinal: Diarrhea, nausea, vomiting, abdominal pain
Musculoskeletal: Joint and muscle pain
Skin: Rash, itching
Respiratory: Cough, shortness of breath
Other: Headache, fatigue, dizziness

TOXICITY

Dasatinib toxicity can include severe neutropenia, thrombocytopenia, and anemia, along with pulmonary arterial hypertension, fluid retention, and heart failure. It may also cause gastrointestinal issues like severe diarrhea, nausea, and vomiting, as well as hepatotoxicity and liver failure. Increased bleeding risk and myelosuppression are also concerns, requiring regular monitoring and possible dose adjustments.