BOSUTINIB
Clinical safety rating: caution
Comprehensive clinical and safety monograph for BOSUTINIB (BOSUTINIB).
Bosutinib is a tyrosine kinase inhibitor that inhibits the BCR-ABL kinase, including many imatinib-resistant mutations, and Src family kinases.
| Metabolism | Primarily metabolized by CYP3A4; minor contributions from other CYP enzymes. |
| Excretion | Primarily fecal (approx. 68% as unchanged drug and metabolites) and renal (approx. 25%, with <0.2% as unchanged drug in urine). |
| Half-life | Terminal elimination half-life approximately 33 hours (range 22-60 hr) after oral administration, supporting once-daily dosing. |
| Protein binding | 96% bound to plasma proteins, primarily to albumin and alpha-1 acid glycoprotein. |
| Volume of Distribution | Approximately 3.6 L/kg (range 2.8-4.6 L/kg), indicating extensive extravascular distribution. |
| Bioavailability | Oral bioavailability is 74% (range 60-85%) under fasted conditions; absorption is increased by food (high-fat meal increases AUC by 1.7-fold), but dosing is recommended with food to reduce variability. |
| Onset of Action | Time to peak plasma concentration (Tmax) is 4-6 hours post-dose; clinical response (e.g., cytogenetic response) may be observed within 3-6 months of continuous therapy. |
| Duration of Action | With once-daily oral dosing, sustained target inhibition (e.g., BCR-ABL kinase) over 24 hours; treatment is typically chronic until disease progression or unacceptable toxicity. |
| Molecular Weight | 530.4 |
400 mg orally once daily with food.
| Dosage form | TABLET |
| Renal impairment | CrCl 30-50 mL/min: 300 mg orally once daily. CrCl <30 mL/min: 200 mg orally once daily. Not recommended for CrCl <15 mL/min. |
| Liver impairment | Child-Pugh A: 400 mg orally once daily. Child-Pugh B: 200 mg orally once daily. Child-Pugh C: 100 mg orally once daily. |
| Pediatric use | No established pediatric dosing; not recommended for patients <18 years. |
| Geriatric use | No specific dose adjustment based solely on age; monitor renal function. Start at 400 mg orally once daily with food. |
| 1st trimester | Avoid. Bosutinib is embryotoxic and fetotoxic in animal studies. Human data are lacking; however, based on mechanism of action (tyrosine kinase inhibitor), there is potential for fetal harm. Effective contraception should be used during treatment. |
| 2nd trimester | Avoid. Bosutinib can cause fetal harm based on animal studies showing teratogenicity and embryolethality. Use only if maternal benefit outweighs potential fetal risk, though such circumstances are rare. |
| 3rd trimester | Avoid. Bosutinib and its metabolites can cross the placenta. Exposure during third trimester may lead to low birth weight, fetal growth restriction, and potential neonatal toxicity. |
Clinical note
Comprehensive clinical and safety monograph for BOSUTINIB (BOSUTINIB).
| Placental transfer | Likely: Bosutinib is a small molecule (molecular weight 530.4 Da) with moderate protein binding (94-96%), suggesting placental transfer. Animal studies confirm fetal exposure. |
| Breastfeeding |
■ FDA Black Box Warning
None.
| Serious Effects |
Hypersensitivity to bosutinib or any excipientsConcomitant use with strong CYP3A4 inducers (e.g., rifampin) may lead to reduced efficacy due to decreased bosutinib exposure
| Precautions | Cardiovascular toxicity: Can cause myocardial infarction, stroke, and heart failure; especially in patients with cardiovascular risk factors., Hepatotoxicity: Elevations in liver enzymes and bilirubin; monitor liver function., Myelosuppression: Thrombocytopenia, neutropenia, anemia; monitor blood counts., Gastrointestinal toxicity: Diarrhea, nausea, vomiting; manage with supportive care., Fluid retention: Edema, pleural effusion, pericardial effusion., Renal toxicity: Elevations in serum creatinine; monitor renal function., Fetal harm: Can cause fetal harm; advise pregnant women of risk., Pancreatitis: Elevated lipase; monitor pancreatic enzymes. |
| Food/Dietary | Take with food to reduce gastrointestinal side effects. Avoid grapefruit and grapefruit juice as they inhibit CYP3A4 and can increase bosutinib levels. |
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| Bosutinib is excreted into human breast milk in low concentrations. A case report indicates a relative infant dose of approximately 0.3-4.1% of maternal weight-adjusted dose. However, due to lack of safety data and potential for adverse effects (e.g., immunosuppression, growth inhibition), breastfeeding is not recommended during therapy and for at least 2 weeks after last dose. |
| Lactation Rating | L4 |
| Teratogenic Risk | Bosutinib is embryotoxic and fetotoxic in animal studies. Human data are limited, but based on its mechanism of tyrosine kinase inhibition, there is potential for teratogenicity. First trimester exposure carries the highest risk of structural abnormalities. Second and third trimester exposure may cause fetal growth restriction, oligohydramnios, and impaired fetal development. |
| Fetal Monitoring | Monitor maternal complete blood count, hepatic function, serum lipase and amylase, serum electrolytes, and blood pressure. Fetal monitoring includes serial ultrasound for growth, amniotic fluid volume, and anatomy. Perform fetal echocardiography due to potential cardiotoxicity. Monitor for signs of maternal fluid retention and pleural effusion. |
| Fertility Effects | Bosutinib may impair male and female fertility based on animal studies. In male rats, testicular atrophy and decreased sperm count were observed. In female rats, disrupted estrous cycles and reduced fertility occurred. Human data are lacking; however, potential for temporary or permanent infertility exists. |
| Clinical Pearls | Bosutinib is a dual Src/Abl tyrosine kinase inhibitor indicated for chronic-phase, accelerated-phase, or blast-phase Ph+ CML with resistance or intolerance to prior therapy. Monitor liver function tests frequently due to risk of hepatotoxicity; dose reduction or interruption may be needed. Diarrhea is common and often dose-limiting; manage with antidiarrheals and hydration. Avoid strong CYP3A4 inhibitors or inducers; adjust bosutinib dose accordingly. QT interval prolongation can occur; monitor ECG and electrolytes. Pancreate-related adverse events including pancreatitis have been reported; monitor lipase and amylase. |
| Patient Advice | Take bosutinib exactly as prescribed, with food to reduce gastrointestinal upset. · Do not crush or chew tablets; swallow whole. · Report any signs of liver problems (yellowing skin/eyes, dark urine, right upper quadrant pain) or pancreatitis (severe abdominal pain, nausea, vomiting). · Expect diarrhea; proactively use antidiarrheal medications and maintain fluid intake to prevent dehydration. · Avoid grapefruit and grapefruit juice while on bosutinib. · Inform your doctor about all medications you are taking, including over-the-counter drugs and supplements, due to potential interactions. · Do not change dose or stop bosutinib without consulting your doctor. |