DASATINIB
Clinical safety rating: avoid
Contraindicated (not allowed)
Dasatinib is a tyrosine kinase inhibitor that targets BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRβ. It inhibits BCR-ABL autophosphorylation and downstream signaling, leading to apoptosis in Philadelphia chromosome-positive (Ph+) leukemia cells.
| Metabolism | Primarily metabolized by CYP3A4; also a substrate of CYP3A4 and CYP2C8. |
| Excretion | Approximately 85% of the dose is eliminated via feces (mainly as metabolites), and about 4% via urine (parent drug and metabolites). Less than 1% is excreted unchanged in urine. |
| Half-life | Terminal elimination half-life is 3-5 hours. This short half-life supports twice-daily dosing, but active metabolite (N-desmethyl dasatinib) has a similar half-life and contributes to PD activity. |
| Protein binding | Approximately 96% bound to plasma proteins, primarily to albumin and alpha-1 acid glycoprotein. |
| Volume of Distribution | Vd is 2505 L (approximately 35.8 L/kg for a 70 kg adult), indicating extensive tissue distribution. This large Vd contributes to long tissue retention despite short plasma half-life. |
| Bioavailability | Oral bioavailability is approximately 14-34% (mean ~30%). A high-fat meal reduces AUC by 15-20% (not clinically significant, but label advises caution with grapefruit juice). |
| Onset of Action | Oral: Onset of BCR-ABL inhibition occurs within 1-2 hours post-dose; maximal inhibition correlates with peak plasma concentrations (Cmax at 0.5-6 hours). |
| Duration of Action | Duration of target inhibition persists for 6-12 hours, supporting BID dosing. Continuous suppression of BCR-ABL requires repeated dosing due to short half-life. |
140 mg orally once daily; reduce to 100 mg once daily if no cytogenetic response after 3 months or 140 mg once daily with dose escalation to 200 mg once daily as tolerated.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (CrCl ≥30 mL/min). For severe renal impairment (CrCl <30 mL/min), reduce initial dose to 140 mg once daily; consider further dose reduction based on tolerability. |
| Liver impairment | Child-Pugh A: 140 mg once daily. Child-Pugh B: 100 mg once daily. Child-Pugh C: 100 mg once daily with close monitoring or consider alternative therapy. |
| Pediatric use | Weight-based dosing: 10-20 kg: 40 mg once daily; 20-30 kg: 60 mg once daily; 30-45 kg: 80 mg once daily; >45 kg: 100 mg once daily. For children ≥1 year with chronic phase CML or Ph+ ALL. |
| Geriatric use | No specific dose adjustment recommended; monitor renal function (CrCl) and adjust accordingly. Elderly patients may have increased risk of pleural effusion and fluid retention; use lowest effective dose and monitor closely. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Antacids and H2 blockers decrease absorption May cause severe myelosuppression and fluid retention.
| Breastfeeding | Dasatinib is excreted in human milk. The milk-to-plasma ratio is approximately 0.9. Due to potential serious adverse reactions in nursing infants, breastfeeding is contraindicated during treatment and for at least 14 days after the last dose. |
| Teratogenic Risk | Dasatinib is embryotoxic and fetotoxic in animal studies. In humans, it is contraindicated in pregnancy due to risk of fetal harm. First trimester exposure may cause major congenital malformations. Second and third trimester exposure may lead to fetal growth restriction, oligohydramnios, and fetal demise. Adequate contraception is required during treatment. |
■ FDA Black Box Warning
Dasatinib can cause pulmonary arterial hypertension (PAH) which may develop at any time during treatment, including after prolonged therapy. PAH may be reversible upon discontinuation. Evaluate patients for signs and symptoms of cardiopulmonary disease before and during treatment.
| Common Effects | Myelosuppression |
| Serious Effects |
["Hypersensitivity to dasatinib or any component of the formulation"]
| Precautions | ["Pulmonary arterial hypertension","Pleural effusions, pericardial effusions, and other fluid retention events","QT prolongation","Myelosuppression (thrombocytopenia, neutropenia, anemia)","Bleeding-related events (including severe CNS and GI hemorrhages)","Use with potent CYP3A4 inducers or inhibitors requires dose adjustment","Fetal harm if used during pregnancy"] |
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| Fetal Monitoring | Monitor complete blood count (CBC) with differential, liver function tests (LFTs), serum electrolytes, and renal function at baseline and periodically. Monitor for signs of fluid retention, pleural effusion, pulmonary arterial hypertension, and cardiac dysfunction. Perform fetal ultrasound to assess growth and amniotic fluid volume if used inadvertently during pregnancy. |
| Fertility Effects | Dasatinib may impair male and female fertility. In animal studies, testicular degeneration and reduced spermatogenesis were observed. Reversible menstrual irregularities and ovarian failure may occur in females. Use effective contraception during treatment and for at least 30 days after the last dose. |