Usage
Busulfan is prescribed for the treatment of chronic myeloid leukemia (CML). It is also used as a conditioning agent prior to hematopoietic stem cell transplantation (HSCT) for various malignant and non-malignant disorders. It belongs to the alkylating agent class of chemotherapy drugs. Busulfan works by interfering with DNA replication and RNA transcription. This disrupts cell division and leads to cell death, primarily targeting rapidly dividing cells like cancer cells.
Alternate Names
Busulfan is also known as 1,4-Butanediol dimethanesulfonate. A common brand name for Busulfan is Myleran.
How It Works
Pharmacodynamics: Busulfan is a bifunctional alkylating agent, meaning it can attach alkyl groups to two different sites on DNA. This action leads to DNA cross-linking and strand breaks, disrupting DNA replication and transcription, ultimately leading to cell death. Its antitumor activity is not specific to any phase of the cell cycle.
Pharmacokinetics:
- Absorption: Oral busulfan is well absorbed from the gastrointestinal tract, but absorption can be variable. Intravenous administration provides more predictable drug levels.
- Metabolism: Busulfan is primarily metabolized in the liver by glutathione-S-transferase, forming various metabolites. Cytochrome P450 enzymes play a minor role in its metabolism.
- Elimination: Metabolites are primarily excreted in the urine.
Mode of Action: Busulfan forms carbonium ions that alkylate DNA, causing cross-linking of DNA strands and preventing DNA replication and transcription. This primarily affects rapidly dividing cells like cancer cells.
Receptor binding, enzyme inhibition, or neurotransmitter modulation: The primary mechanism of action involves DNA alkylation, not receptor binding, direct enzyme inhibition, or neurotransmitter modulation.
Elimination pathways: Busulfan is eliminated primarily through hepatic metabolism and subsequent renal excretion of metabolites.
Dosage
Standard Dosage
Adults:
- Oral: The initial dose for CML is 4-8 mg daily, adjusted based on blood counts. Maintenance dosing is usually lower. For HSCT conditioning, higher doses (3.5-4 mg/kg/day for 4 days) are used.
- IV: For HSCT conditioning, 0.8 mg/kg (based on ideal or actual body weight, whichever is lower) every 6 hours for 4 days is common. Dosage adjustments based on therapeutic drug monitoring using area under the curve (AUC) are crucial.
Children:
Dosing is generally weight-based and individualized, similar to adult dosing, with careful monitoring of blood counts and organ function. For HSCT, dosage based on actual body weight is recommended starting with 1.0 mg/kg for children ≤ 4 years and 0.8 mg/kg for those > 4 years with dose adjustments based on measured AUC.
Special Cases:
- Elderly Patients: Initiate with the lowest recommended dose due to potential age-related decline in organ function.
- Patients with Renal Impairment: Caution is advised, but no specific dose adjustment is typically needed.
- Patients with Hepatic Dysfunction: Dose reduction may be necessary due to impaired metabolism. Monitor liver function tests closely.
- Patients with Comorbid Conditions: Consider individual patient characteristics and comorbidities when determining the dose and monitor closely for adverse effects.
Clinical Use Cases
Busulfan is primarily used in the context of HSCT conditioning regimens. Dosing is tailored to the specific transplant protocol. It is not typically used in settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations.
Dosage Adjustments
Dosage adjustments are crucial, particularly with IV busulfan, and are based on therapeutic drug monitoring, targeting a specific AUC. Adjustments are necessary for patients with hepatic dysfunction and for obese patients, using adjusted ideal body weight.
Side Effects
Common Side Effects
Nausea, vomiting, diarrhea, loss of appetite, mucositis (sores in the mouth and throat), dry mouth, headache, insomnia, anxiety, dizziness, peripheral edema, chest pain, joint or muscle pain, skin rash, itching, dry skin, skin darkening, hair loss, myelosuppression (decreased blood cell counts), and pulmonary toxicity.
Rare but Serious Side Effects
Seizures, hepatic veno-occlusive disease (VOD), pulmonary fibrosis, and secondary malignancies (including leukemia).
Long-Term Effects
Infertility, pulmonary fibrosis, and secondary malignancies.
Adverse Drug Reactions (ADR)
Severe myelosuppression, VOD, and anaphylaxis are rare but serious ADRs requiring immediate intervention.
Contraindications
Hypersensitivity to busulfan, pregnancy, and breastfeeding.
Drug Interactions
Busulfan interacts with numerous medications, including:
- CYP3A4 inhibitors (e.g., itraconazole, metronidazole, posaconazole): Can increase busulfan levels and toxicity.
- CYP3A4 inducers (e.g., phenytoin): Can decrease busulfan levels and efficacy.
- Acetaminophen: Can decrease busulfan clearance.
- Iron-chelating agents: Can decrease busulfan clearance.
It’s important to review a comprehensive drug interaction list before prescribing busulfan.
Pregnancy and Breastfeeding
Busulfan is contraindicated in pregnancy (Pregnancy Category D) and breastfeeding due to its teratogenic effects and potential harm to the nursing infant.
Drug Profile Summary
- Mechanism of Action: Alkylating agent, causing DNA damage and cell death.
- Side Effects: Myelosuppression, mucositis, pulmonary toxicity, VOD, seizures.
- Contraindications: Hypersensitivity, pregnancy, breastfeeding.
- Drug Interactions: CYP3A4 inhibitors/inducers, acetaminophen, iron chelators.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: Variable based on indication and route of administration; requires therapeutic drug monitoring.
- Monitoring Parameters: Blood counts, liver function tests, pulmonary function tests.
Popular Combinations
Busulfan is often used in combination with cyclophosphamide for HSCT conditioning.
Precautions
- Assess for pre-existing medical conditions, including hepatic or renal dysfunction.
- Monitor blood counts, liver function, and pulmonary function regularly.
- Prophylactic anticonvulsants are recommended, particularly with high-dose regimens.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Busulfan?
A: Dosage varies significantly depending on the indication (CML treatment vs. HSCT conditioning), route of administration (oral vs. IV), and patient-specific factors (age, weight, organ function). Consult specific protocols and utilize therapeutic drug monitoring (TDM) for optimal dosing.
Q2: How is Busulfan administered?
A: Busulfan can be administered orally or intravenously. Intravenous administration is preferred for HSCT conditioning due to more predictable drug levels.
Q3: What are the most common side effects of Busulfan?
A: Common side effects include myelosuppression, mucositis, nausea, vomiting, diarrhea, and pulmonary toxicity.
Q4: What are the serious side effects of Busulfan?
A: Serious side effects include VOD, seizures, pulmonary fibrosis, and secondary malignancies.
Q5: What are the key drug interactions with Busulfan?
A: Important drug interactions include those with CYP3A4 inhibitors and inducers, acetaminophen, and iron-chelating agents.
Q6: Can Busulfan be used during pregnancy or breastfeeding?
A: No, Busulfan is contraindicated during pregnancy and breastfeeding due to its teratogenic effects and potential for serious adverse events in the infant.
Q7: What monitoring parameters are essential for patients receiving Busulfan?
A: Essential monitoring parameters include regular blood counts, liver function tests, and pulmonary function tests.
Q8: What is the role of therapeutic drug monitoring (TDM) in Busulfan therapy?
A: TDM, particularly for IV busulfan, is essential for individualizing the dose and optimizing efficacy while minimizing toxicity. This involves measuring busulfan AUC and adjusting the dose accordingly to achieve the target AUC.
Q9: How does busulfan cause VOD?
A: The exact mechanism is unclear, but it’s believed that busulfan damages the endothelial cells lining the hepatic venules, leading to inflammation, occlusion, and subsequent liver damage.
Q10: What are the long-term risks associated with busulfan therapy?
A: Long-term risks include infertility, secondary malignancies (particularly leukemia), and pulmonary fibrosis.
