Busulfan

Approved Indications:

• Chronic Myeloid Leukemia (CML)
• Treatment of CML, particularly in chronic phase or palliative treatment of CML in patients not eligible for targeted therapy.
• Hematopoietic Stem Cell Transplantation (HSCT) Conditioning Regimen
• Adults and Pediatrics: As part of a conditioning regimen prior to allogeneic hematopoietic stem cell transplantation in hematologic malignancies such as acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or CML.
• Often combined with cyclophosphamide or fludarabine.

Off-label/Clinically Accepted Uses:

• Polycythemia Vera and Essential Thrombocythemia (ET): In patients unresponsive or intolerant to hydroxyurea.
• Myelofibrosis: Occasionally used as palliative therapy.

Dosage varies by indication and regimen:

For HSCT Conditioning (IV Busulfan):

• Adults: 0.8 mg/kg IV every 6 hours for 4 consecutive days (total 16 doses), often in combination with cyclophosphamide or fludarabine.
• Pediatrics: 0.8–1.0 mg/kg/dose IV every 6 hours × 4 days (doses adjusted based on age, weight, and pharmacokinetics).

For CML (Oral Busulfan):

• Initial: 2–4 mg orally daily.
• Maintenance: Dose adjusted based on WBC count; typical maintenance dose is 1–2 mg/day.
• Therapy usually continued until leukocyte count is controlled (often 3–4 weeks).

Administration Notes:

• Administer IV form via central line with appropriate hydration and anticonvulsant prophylaxis (e.g., phenytoin or levetiracetam).
• Therapeutic drug monitoring (TDM) is recommended for IV busulfan to ensure optimal plasma exposure (AUC).

Renal/Hepatic Impairment:

• Use with caution; dose adjustments may be necessary based on pharmacokinetic monitoring.

Busulfan is a bifunctional alkylating agent that forms DNA-DNA and DNA-protein crosslinks by transferring alkyl groups to the N7 position of guanine in DNA. These crosslinks inhibit DNA replication and transcription, ultimately leading to cell cycle arrest and apoptosis, particularly in rapidly dividing hematopoietic cells. This cytotoxic effect is used to deplete bone marrow cells prior to transplantation and to control myeloproliferative disorders.

• Absorption (Oral): Well absorbed (80–90%) with high inter-patient variability.
• Bioavailability: Oral: ~80–90%.
• Distribution: Widely distributed; crosses blood-brain barrier.
• Protein Binding: ~32%.
• Metabolism: Primarily hepatic via conjugation with glutathione (non-CYP pathway); produces inactive metabolites.
• Half-life:
• IV: 2–3 hours (shorter in children).
• Oral: Variable (~2.5 hours).
• Excretion: Primarily renal (as metabolites); <2% excreted unchanged.
• Therapeutic Monitoring: AUC-based dosing for IV form improves efficacy and reduces toxicity.

• Pregnancy Risk: Category D (positive evidence of human fetal risk). Teratogenic and embryotoxic. Avoid use unless benefits outweigh risks.
• Lactation: Unknown if excreted in breast milk. Due to potential for serious adverse effects in infants, breastfeeding should be discontinued during treatment.
• Contraception: Effective contraception is advised during treatment and for at least 6 months after the last dose.

• Primary Class: Alkylating Agent
• Subclass: Nitrosourea-like bifunctional DNA alkylator
• Group: Antineoplastic agent

• Known hypersensitivity to busulfan or any excipient
• Uncontrolled infection
• Severe hepatic impairment without dose monitoring
• Concurrent use of other alkylating agents without proper scheduling

• Seizures: High-dose IV busulfan may cause seizures; prophylactic anticonvulsants are required.
• Hepatic Veno-Occlusive Disease (VOD): Risk increases in patients with liver dysfunction or when combined with cyclophosphamide.
• Pulmonary Toxicity: Risk of interstitial pulmonary fibrosis (“busulfan lung”), especially with prolonged oral use.
• Bone Marrow Suppression: Severe and prolonged myelosuppression may occur; monitor CBCs closely.
• Secondary Malignancy: Long-term use is associated with an increased risk of secondary malignancies.
• Drug Monitoring Required: Especially for IV form to maintain target AUC and reduce toxicity.

Hematologic:

• Neutropenia, thrombocytopenia, anemia (dose-limiting)

Gastrointestinal:

• Nausea, vomiting, mucositis, diarrhea

Hepatic:

• Elevated liver enzymes, hepatic VOD, jaundice

Neurological:

• Seizures (especially at high doses), dizziness, confusion

Pulmonary:

• Pulmonary fibrosis, dyspnea

Dermatologic:

• Hyperpigmentation, rash, alopecia

Other Serious Reactions:

• Febrile neutropenia
• Secondary leukemia
• Fertility impairment

• Itraconazole, Metronidazole: May increase busulfan levels (inhibit metabolism), raising risk of toxicity.
• Acetaminophen: Reduces glutathione, impairing busulfan metabolism.
• Phenytoin: Induces busulfan clearance—sometimes intentionally used to reduce levels but may cause variable exposure.
• Cyclophosphamide: Combined use increases risk of hepatic VOD.
• CYP450 Interactions: Busulfan metabolism is not heavily dependent on CYP enzymes but still susceptible to modulation via glutathione pathways.

• Therapeutic Drug Monitoring (TDM): Now widely recommended for IV busulfan to maintain a target AUC (900–1350 µM·min per dose) for optimal safety and efficacy.
• Pediatric Dosing Updates: Weight- and age-based dosing protocols with individualized adjustments based on clearance and TDM.
• EMA & FDA Guidelines: Encourage use in combination conditioning regimens (e.g., Busulfan + Fludarabine) as standard for HSCT preparation in certain hematologic malignancies.

• IV Formulation (Injection):
• Store unopened vials at 2°C to 8°C (refrigerated).
• Protect from light.
• Do not freeze.
• Once diluted: Use immediately or store at 2°C to 8°C for up to 8 hours.
• Oral Tablets:
• Store at 20°C to 25°C.
• Protect from moisture and heat.
• Keep in tightly closed container.