Generic Name

Dasatinib

Mechanism

• Dasatinib (Vyndamax) is a *second‑generation tyrosine kinase inhibitor* that targets the BCR‑ABL1 fusion protein and Src family kinases.
• It binds directly to the ATP‑binding pocket of BCR‑ABL1, preventing autophosphorylation and downstream signaling through substrates such as STAT5, STAT6, and CRK.
• By inhibiting these pathways, Vyndamax induces apoptosis in Philadelphia‑chromosome positive leukemic cells.
• The drug retains activity against many imatinib‑resistant point mutations (e.g., E255V, L248V, G250E, H396P) but is *ineffective against the T315I mutation*, for which ponatinib is recommended.

Pharmacokinetics

• Oral absorption: ~90 % bioavailability; peak plasma concentration (Tmax) ~2–4 hrs.
• Half‑life: ~5–6 hrs, allowing once‑daily dosing.
• Metabolism: Primarily via CYP3A4; minor contribution from CYP2C9 and CYP2A6.
• Excretion: 13 % renal (~0.33 mg ×  g‑kg‑1 day‑1), 88 % biliary via hepatobiliary excretion.
• Food effect: Absorption is modestly reduced with high‑fat meals; recommend taking on an empty stomach.

Indications

• Chronic Myeloid Leukemia (CML):
• Newly diagnosed or imatinib‑resistant CML in chronic or accelerated phase.
• Imatinib‑naïve patients who prefer rapid cytogenetic response.
• Ph‑Positive Acute Lymphoblastic Leukemia (ALL):
• First‑line therapy in patients aged <18 yrs or adults with Philadelphia‑chromosome positive ALL.
• Blastic Phase CML:
• Initial therapy for patients with blast crisis who have inadequate response to imatinib or nilotinib.

Contraindications

• Allergy to dasatinib or excipients.
• Severe cardiac disease: Concomitant use with strong CYP3A4 inhibitors or QT‑prolonging agents should be avoided.
• Severe concurrent infections: May worsen marrow suppression.
• Pregnancy: Teratogenic in animal studies; avoid if pregnancy is suspected.
• Fluid‑retention prone patients: Pleural effusions, heart failure, or significant hepatic disease may be worsened.

Dosing

• Typical Adult Dose: 100 mg once daily (QD) orally.
• *High‑dose escalation*: If inadequate hematologic or cytogenetic response after 3 mo, *increase to 140 mg QD* after a 5‑day break to reduce toxicity.
• Pediatric Dose: Weight‑based (80 mg/m² QD) up to 80 mg QD.
• Administration: Take on an empty stomach; water is sufficient.
• Special populations:
• *Renal impairment*: No adjustment required.
• *Hepatic dysfunction*: Dose reduction or monitoring suggested; patients with Child‑Pugh B/C may experience higher plasma levels.

Adverse Effects

• Myelosuppression is dose‑dependent; monitor CBC every 2‑4 weeks during the first 3 mo.
• Pleural effusion incidence ~10–15 %; risk increases with higher dose, female sex, and obesity.

Monitoring

• Baseline: CBC with differential, liver/renal panels, chest X‑ray, ECG (QTc).
• During therapy:
• CBC every 2 weeks (1st month), then monthly.
• ALT/AST, bilirubin, creatinine each month.
• ECG quarterly or sooner if symptoms of dyspnea/orthopnea.
• Re‑evaluate for pleural effusion with chest imaging if dyspnea, orthopnea, or weight gain.

Clinical Pearls

1. Rapid Cytogenetic Response – Dasatinib ≥ 8× faster than imatinib; consider as first‑line if a swift response is needed.

2. T315I Mutation – Vyndamax fails; patients should transition to ponatinib or clinical trials.

3. Dose Escalation Strategy – Move from 100 mg to 140 mg only after 3 months of inadequate response; provide a 5‑day drug break to mitigate myelosuppression.

4. Drug–Drug Interactions – Strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir) increase exposure; consider dose reduction.

5. Fluid Retention – Up to 1/3 of patients develop pleural effusion; ensure baseline lean body mass assessment; treat with diuretics or temporary cessation.

6. Imaging for Pulmonary Hypertension – Repeat echocardiogram or CT angiography if symptoms like exertional dyspnea emerge.

7. Herbal Supplements – Avoid St. John’s wort and other CYP3A4 inducers which may lower dasatinib levels.

8. Vaccinations – Live vaccines contraindicated during therapy; use inactivated vaccines per guidelines.

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• Reference:

1. NCT03807433 – Dasatinib in Ph‑positive ALL.

2. FDA Label Vyndamax, 2011–2024.

3. WHO Essential Medicines List 2023.

This structured drug card offers precise pharmacology with critical clinical insights for students and healthcare professionals.