Quizartinib
Quizartinib
Generic Name
Quizartinib
Mechanism
- Target: Inhibits the *FMS‑like tyrosine kinase 3 (FLT3)* receptor, a transmembrane receptor tyrosine kinase frequently mutated in AML.
- Binding site: Competitively binds the ATP‑binding pocket of FLT3, preventing phosphorylation of downstream signaling pathways (STAT5, RAS-MAPK, PI3K/AKT).
- Selectivity: >60‑fold greater affinity for mutant FLT3 (ITD and tyrosine‑kinase domain mutations) compared with wild‑type FLT3 or other kinases, reducing off‑target toxicity.
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Pharmacokinetics
| Parameter | Key Findings |
| Absorption | Oral bioavailability ≈ 30 % after a 30 mg dose; peak plasma concentration (tₘₐₓ) reached ~6 h post‑dose. |
| Distribution | Volume of distribution ~ 1.2 L/kg; highly protein‑bound (≈ 99 %). |
| Metabolism | Primarily hepatic via CYP3A4/5; minimal glucuronidation. |
| Elimination | Half‑life ~ 21 h; excreted mostly in feces (~ 60 %); renal clearance is low. |
| Drug–drug interactions | Co‑administration with strong CYP3A4 inhibitors (e.g., ketoconazole) can raise levels by up to 4‑fold; strong inducers (e.g., rifampin) reduce exposure by > 60 %. |
| Special populations | No dose adjustment needed for mild‑moderate hepatic impairment; caution in severe hepatic disease or patients on strong CYP3A4 inhibitors. No data in severe renal impairment; avoid in patients with CrCl < 30 mL/min. |
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Indications
- Approved in the EU for relapsed or refractory FLT3‑ITD+ AML in adults and adolescents ≥ 12 y.
- Investigational in ongoing Phase III trials for newly diagnosed FLT3‑mutated AML in combination with standard induction or as monotherapy post‑remission.
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Contraindications
| Contraindication / Warning | Rationale | |
| QT prolongation (baseline QTc > 470 ms) | Quizartinib can prolong QTc; increased risk of torsades de pointes. | |
| Severe hepatic impairment (Child‑Pugh C) | Metabolism via CYP3A4; accumulation may occur. | |
| Pregnancy | Animal studies showed embryo‑fetal toxicity; use only if the potential benefit outweighs risk and effective contraception is ensured for both sexes. | |
| Concurrent use of strong CYP3A4 inhibitors | Significant rise in systemic exposure. | |
| Tumor lysis risk | First‑dose tumor lysis syndrome (TLS) common in patients with high tumor burden. |
Warrants:
• Baseline and periodic ECG monitoring.
• Regular assessments of renal/hepatic function and electrolytes.
• Adequate hydration and early detection of TLS.
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Dosing
| Regimen | Details |
| Initial therapy | 30 mg orally, twice daily (BID), continuously, 28‑day cycle. |
| Dose escalation (optional) | For patients tolerating 30 mg BID, escalation to 60 mg BID can be considered after ≥ 4 weeks if disease control is inadequate and no dose‑limiting toxicity occurs. |
| Administration | Take with food to enhance absorption; hold dose if nausea/vomiting unresolved. |
| Dose interruptions | Interrupt until recovery from grade ≥ 3 toxicity; resume at 50 % of the previous dose. |
| Resumption after interruption | Restart at lowest tolerable dose; titrate up if remission is achieved and toxicity is manageable. |
| Switching to alternative therapy | If cumulative toxicities or lack of response, consider bridging to allo‑HCT or switching to another FLT3 inhibitor. |
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Adverse Effects
| Category | Common (≥ 10 %) | Serious / Rare |
| Hematologic | Neutropenia, anemia, thrombocytopenia | Febrile neutropenia, severe cytopenias |
| Gastrointestinal | Nausea, vomiting, diarrhea, dyspepsia | Severe dehydration, electrolyte imbalance |
| Electrolyte / Cardiac | Hypokalemia, hypomagnesemia | QTc prolongation → torsades de pointes |
| Hepatic | Mild ↑ AST/ALT, hyperbilirubinemia | Acute hepatitis, transaminitis |
| Other | Headache, dizziness, fatigue | Tumor lysis syndrome (first‑dose), visual disturbances |
| Rare | Rash, pancreatitis, interstitial lung disease | Severe allergic reactions (anaphylaxis) |
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Monitoring
- Baseline: CBC, CMP, serum electrolytes, liver enzymes, renal function, ECG (QTc).
- During therapy:
- CBC & CMP weekly (first cycle) then every 2 weeks.
- ECG every 2 weeks in Cycle 1, then monthly if stable.
- Serum potassium & magnesium twice weekly in patients on high‑dose therapy.
- At any sign of tumor lysis: Monitor uric acid, LDH, creatinine, electrolytes daily until stable.
- Special populations: More frequent monitoring for those on CYP3A4 inhibitors or with hepatic dysfunction.
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Clinical Pearls
- Dose is the key to balancing efficacy and toxicity – many patients reach optimal disease control at 30 mg BID; escalation to 60 mg should be reserved for refractory cases.
- Avoid concomitant QT‑prolonging agents (e.g., macrolides, diuretics like amiodarone) to mitigate torsades risk.
- Hydration is essential – pre‑emptive IV fluids for high‑tumor burden patients can dramatically reduce first‑dose TLS incidence.
- CYP3A4 inhibitors = a red flag – even ketoconazole can double quizartinib exposure; consult pharmacy before adding azole antifungals or macrolides.
- Monitor for hematologic recovery after intensive chemotherapy – if neutropenia persists after 2 weeks of quizartinib, consider dose hold and growth factor support.
- Pregnancy and lactation – use a barrier method of contraception; the drug is excreted in breast milk and may be harmful.
- Emerging data on combination therapy with venetoclax and hypomethylating agents suggests higher remission rates but also overlapping toxicity; careful dose optimization and monitoring are mandatory.
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• *Quizartinib* represents a milestone in precision oncology for FLT3‑positive AML, providing a targeted therapeutic option where options have historically been limited. By mastering its pharmacodynamics, safety profile, and monitoring requirements, clinicians can maximize patient outcomes while minimizing adverse events.