Sprycel
Sprycel
Generic Name
Sprycel
Mechanism
- Dual Src/ABL inhibition: Bosutinib phosphorylates and inactivates the intrinsic kinase activities of both Src-family kinases (Src, Lck, Lyn) and BCR‑ABL, preventing downstream signaling that drives proliferation and survival of leukemic blasts.
- Non‑ATP‑competitive relative to early TKIs, conferring activity against a broader set of BCR‑ABL mutations that confer resistance to imatinib or nilotinib.
- By blocking Src, bosutinib also reduces adhesion‑mediated chemoresistance and modulates the bone‑marrow microenvironment.
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Pharmacokinetics
| Parameter | Typical Value |
| Absorption | Rapid oral absorption; peak plasma concentration (Cmax) at ~5–8 h post‑dose.
| Bioavailability | ~35 % (measured in fasted subjects). |
| Distribution | Volume of distribution ~12 L/kg; high tissue penetration. |
| Protein Binding | ~96 % (primarily to albumin). |
| Metabolism | Hepatic CYP3A4/5 → active metabolites; minor CYP2C9 involvement. |
| Excretion | ~70 % fecal (biliary), ~30 % renal (proceeding unchanged). |
| Half‑Life | ~24 h (steady‑state). |
| Dose‑Dependence | Linear up to 500 mg q.d. |
> Key point: Bosutinib’s long half‑life allows once‑daily dosing, but CYP3A4 inhibitors (e.g., ketoconazole) increase concentrations and require dose adjustment or monitoring.
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Indications
- Chronic phase chronic myeloid leukemia (CP‑CML):
- First‑line therapy in treatment‑naïve patients.
- Second‑line for patients with inadequate response or intolerance to imatinib or nilotinib.
- Advanced phase CML (accelerated or blast):
- If dasatinib or nilotinib are not options.
- Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph⁺‑ALL) in selected cases.
- CML with BCR‑ABL mutations that confer resistance to first‑generation TKIs (e.g., T315I, Y253H).
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Contraindications
| Category | Details |
| Absolute Contraindications |
• Known hypersensitivity to bosutinib or any excipients. • Severe hepatic impairment (Child‑Pugh C). |
| Warnings |
• Hypertension (must be controlled). • Fluid overload/edema can trigger pleural effusion. • Cardiac dysfunction (especially with pre‑existing heart failure). • Gastrointestinal ulcer disease. |
| Precautions |
• Hepatotoxicity: monitor LFTs; avoid concomitant hepatotoxic drugs. • Co‑administration with strong CYP3A4 inducers (e.g., rifampin) reduces efficacy. • Pregnancy: Category D, avoid if possible. |
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Dosing
| Disease Stage | Dosage | Administration | Titration |
| CP‑CML (first‑line) | 400 mg orally once daily | With or without food (take with a light meal to reduce GI upset) | 400 mg → 500 mg if inadequate response after ≥3 mo and no increased toxicity. |
| CP‑CML (second‑line) | 400 mg q.d. | Same | Same. |
| Advanced phase | 500–600 mg q.d. (if tolerated) | Same | Titrate up by 100 mg increments every 4 weeks as tolerated. |
| Ph⁺‑ALL (adjuvant) | 400 mg q.d. | Same | May combine with chemotherapy per protocol. |
• Dose modification: Reduce to 200 mg q.d. for Grade 3–4 hematologic or non‑hematologic toxicity; hold therapy if Grade 4 toxicity or >5 days of Grade 3 neutropenia/platelet‑low events.
• Discontinuation: If uncontrolled hypertension or significant fluid collections >24 h of pleural effusion.
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Adverse Effects
Common (≥10 %)
• Gastrointestinal: nausea, vomiting, diarrhea, abdominal pain.
• Hematologic: neutropenia (10–20 %), anemia (5–10 %), thrombocytopenia (5–10 %).
• Fluid retention: peripheral edema, edema of lower extremities.
• Rash, pruritus.
Serious (≤1 %)
• Grade 3–4 cytopenias (neutropenia, thrombocytopenia).
• Pleural effusion (requires thoracentesis or discontinuation).
• Pulmonary hypertension (rare).
• Hepatic dysfunction (↑AST/ALT >5× ULN).
• Cardiovascular events: heart failure, arrhythmias.
> Management tip: Use growth factors (G‑CSF, platelet transfusion) for cytopenias; diuretics for fluid overload; adjust dose or stop for hepatotoxicity.
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Monitoring
| Parameter | Frequency | Rationale |
| Complete Blood Count (CBC) | Baseline; weekly first month; then bi‑weekly until week 12; monthly thereafter. | Detect neutropenia, anemia, thrombocytopenia. |
| Liver Function Tests (LFTs) | Baseline; monthly first 3 mo; then every 3 mo. | Monitor hepatotoxicity. |
| Kidney Function (CrCl/ eGFR) | Baseline; quarterly. | Adjust dose in severe renal impairment. |
| Blood Pressure | Baseline; at each visit. | Manage hypertension, risk of pleural effusion. |
| Chest Imaging | Baseline; if patient develops dyspnea or cough. | Detect pleural effusion. |
| Adverse Event Recording | Every visit. | Early identification of serious toxicity. |
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Clinical Pearls
- Food Interaction: Bosutinib can be taken with or without food; however, a light meal reduces nausea without significantly affecting absorption.
- Cytochrome P450 Interaction: Strong CYP3A4 inducers (e.g., carbamazepine) decrease plasma levels; strong inhibitors (e.g., clarithromycin) increase levels. Adjust dose accordingly.
- Renal Impairment: No dose adjustment necessary for mild–moderate CKD; for eGFR <30 mL/min/1.73 m², reduce to 300 mg q.d. with close CBC and LFT monitoring.
- Bone Marrow Engraftment: Not recommended in patients awaiting allo‑HSCT due to potential interference with engraftment.
- Combination Therapy: Bosutinib can be combined with interferon‑α or dasatinib for synergistic activity in resistant CML—use only in clinical trials.
- Tolerability: Compared to nilotinib, bosutinib has a lower incidence of cardiovascular events (QT prolongation, arterial occlusive disease) but a slightly higher rate of gastrointestinal upset.
- Patient Education: Instruct patients to report any unexplained swelling, shortness of breath, fever, or bruising promptly; these may signal cytopenias or pleural effusion.
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