Ixabepilone

Usage

Ixabepilone is prescribed for the treatment of metastatic or locally advanced breast cancer in patients who have received prior chemotherapy, including anthracyclines, taxanes, and often capecitabine. It can be used as monotherapy or in combination with capecitabine. It is classified as an antineoplastic agent, specifically a microtubule stabilizer, belonging to the epothilone class. Ixabepilone works by binding to beta-tubulin subunits in microtubules, stabilizing them. This inhibits the normal dynamics of microtubules, which are essential for cell division, leading to cell cycle arrest and ultimately cell death (apoptosis).

Alternate Names

Ixabepilone is also known by its brand name, Ixempra®.

How It Works

Pharmacodynamics: Ixabepilone’s primary effect is the disruption of microtubule function, essential for cell division and intracellular transport. This leads to cell cycle arrest and apoptosis in cancer cells.

Pharmacokinetics:

• Absorption: Ixabepilone is administered intravenously, thus absorption is not a relevant factor.
• Distribution: It has a large volume of distribution, indicating extensive tissue penetration.
• Metabolism: Ixabepilone is primarily metabolized in the liver, mainly by CYP3A4 enzymes.
• Excretion: Ixabepilone is eliminated through both biliary (fecal) and renal (urine) routes.

Mode of Action: Ixabepilone binds to beta-tubulin subunits of microtubules, suppressing microtubule dynamics, specifically the dynamic instability of alpha-beta-II and alpha-beta-III microtubules. This microtubule stabilization leads to G2/M cell cycle arrest and subsequent apoptosis.

Receptor Binding/Enzyme Inhibition: Ixabepilone’s primary mechanism involves binding to beta-tubulin, not receptors. Its metabolism involves hepatic CYP3A4 enzymes.

Dosage

Standard Dosage

Adults:

The recommended dosage is 40 mg/m² administered as a 3-hour intravenous infusion every 3 weeks. Doses for patients with body surface area (BSA) exceeding 2.2 m² should be capped and calculated based on 2.2 m². The dose of Ixabepilone is the same for monotherapy and in combination therapy with capecitabine.

Children:

The safety and efficacy of ixabepilone have not been established in pediatric patients.

Special Cases:

• Elderly Patients: Patients ≥65 years of age may experience higher incidences of grade 3/4 adverse reactions and should be closely monitored. No specific dosage adjustments are routinely recommended based on age alone.

• Patients with Renal Impairment: No dosage adjustment is typically needed for patients with mild to moderate renal insufficiency. Ixabepilone/capecitabine combination therapy is not recommended if calculated creatinine clearance (CrCL) is <50 mL/min. Monotherapy has not been evaluated for creatinine >1.5 × ULN.

• Patients with Hepatic Dysfunction: Dosage adjustments are required. For monotherapy:

  • Mild hepatic impairment (AST and ALT ≤2.5 × ULN and bilirubin ≤1 × ULN): 40 mg/m²
    • Mild hepatic impairment (AST and ALT ≤10 × ULN and bilirubin ≤1.5 × ULN): 32 mg/m²
  • Moderate hepatic impairment (AST and ALT ≤10 × ULN and bilirubin >1.5 to ≤3 × ULN): 20-30 mg/m²
  • Severe hepatic impairment (AST or ALT >10 × ULN or bilirubin >3 × ULN): Not recommended. For combination therapy with capecitabine: Contraindicated if AST or ALT >2.5 × ULN or bilirubin >1 × ULN.

• Patients with Comorbid Conditions: Use with caution in patients with diabetes or heart disease, as these conditions may be exacerbated by Ixabepilone. Pre-existing peripheral neuropathy also warrants caution.

Clinical Use Cases

Ixabepilone’s clinical use is specific to metastatic or locally advanced breast cancer resistant to other chemotherapies. The dosage remains consistent across various clinical settings and is not specifically altered for intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations.

Dosage Adjustments

Dosage adjustments are based on adverse events (AEs), hepatic function, and concomitant medications. For certain toxicities, an initial dose reduction of 20% should be made, followed by an additional 20% dose reduction if toxicities recur. Refer to the prescribing information for detailed guidelines on specific AEs and dose modifications.

Side Effects

Common Side Effects:

Fatigue, nausea, vomiting, diarrhea, constipation, alopecia, peripheral neuropathy (numbness, tingling, pain in hands and feet), myalgia/arthralgia, mucositis, anorexia, nail changes, hand-foot syndrome.

Rare but Serious Side Effects:

Severe hypersensitivity reactions (including anaphylaxis), severe neutropenia (with or without fever), thrombocytopenia, severe peripheral neuropathy, cardiac ischemia, ventricular dysfunction, hepatotoxicity.

Long-Term Effects:

Peripheral neuropathy may persist after discontinuation of treatment. Infertility has been reported in some patients.

Adverse Drug Reactions (ADR):

Severe hypersensitivity, myelosuppression, severe peripheral neuropathy, cardiac events, hepatic dysfunction.

Contraindications

• History of severe hypersensitivity to Ixabepilone or Cremophor EL.
• Baseline absolute neutrophil count (ANC) <1500 cells/mm³ or platelet count <100,000 cells/mm³.
• Combination with capecitabine is contraindicated in patients with AST or ALT >2.5 × ULN or bilirubin >1 × ULN.

Drug Interactions

• CYP3A4 Inhibitors: (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir) – Increase Ixabepilone concentrations and toxicity risk. Avoid concomitant use or reduce Ixabepilone dosage to 20 mg/m².

• CYP3A4 Inducers: (e.g., rifampin, phenytoin, carbamazepine, St. John’s wort) – Decrease Ixabepilone concentrations and efficacy. Avoid concomitant use or consider increasing the Ixabepilone dosage gradually from 40 mg/m² to 60 mg/m², administered over 4 hours.

• Grapefruit juice: May increase Ixabepilone concentrations and should be avoided.

• Alcohol: Ixempra contains dehydrated alcohol; advise patients about potential additive CNS effects with other alcohol-containing substances.

Pregnancy and Breastfeeding

• Pregnancy: Pregnancy Category D. Ixabepilone can cause fetal harm. Effective contraception is necessary during treatment and for 7 months after the last dose for women and 4 months after the last dose for men.

• Breastfeeding: Breastfeeding is not recommended during treatment and for 2 weeks after the last dose.

Drug Profile Summary

• Mechanism of Action: Microtubule stabilizer, inhibits cell division.
• Side Effects: Peripheral neuropathy, neutropenia, fatigue, nausea/vomiting, alopecia.
• Contraindications: Hypersensitivity to Cremophor EL, severe neutropenia/thrombocytopenia. Hepatic impairment (combination therapy).
• Drug Interactions: CYP3A4 inhibitors/inducers, grapefruit juice.
• Pregnancy & Breastfeeding: Contraindicated in pregnancy. Breastfeeding not recommended.
• Dosage: 40 mg/m² IV over 3 hours every 3 weeks (adjust for hepatic impairment, drug interactions).
• Monitoring Parameters: CBC, hepatic function tests, signs of neuropathy, hypersensitivity.

Popular Combinations

Ixabepilone is most commonly combined with capecitabine in patients with anthracycline and taxane resistant metastatic breast cancer.

Precautions

• General Precautions: Monitor closely for myelosuppression, peripheral neuropathy, and hypersensitivity reactions. Premedicate with H1 and H2 antagonists to reduce hypersensitivity risk.
• Pregnant Women: Contraindicated.
• Breastfeeding Mothers: Not recommended.
• Children & Elderly: No pediatric data. Increased toxicity risk in elderly.
• Lifestyle Considerations: Advise patients on potential additive CNS effects with alcohol. Avoid grapefruit juice. Caution regarding driving and operating machinery due to potential drowsiness.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Ixabepilone?

A: The standard dosage is 40 mg/m² administered intravenously over 3 hours every 3 weeks. Dosage adjustments are needed for hepatic impairment and concomitant medications.

Q2: What is the mechanism of action of Ixabepilone?

A: Ixabepilone stabilizes microtubules, disrupting cell division and leading to apoptosis.

Q3: What are the most common side effects of Ixabepilone?

A: Peripheral neuropathy, neutropenia, fatigue, nausea/vomiting, alopecia are common side effects.

Q4: What are the major contraindications for using Ixabepilone?

A: Hypersensitivity to Ixabepilone or Cremophor EL, pre-existing severe neutropenia or thrombocytopenia. Combination with capecitabine contraindicated with hepatic impairment.

Q5: How should Ixabepilone be administered?

A: Ixabepilone is given as an intravenous infusion over 3 hours.

Q6: Are there any significant drug interactions with Ixabepilone?

A: Yes, CYP3A4 inhibitors and inducers can significantly impact Ixabepilone concentrations. Grapefruit juice should also be avoided.

Q7: Can Ixabepilone be used during pregnancy or breastfeeding?

A: Ixabepilone is contraindicated during pregnancy. Breastfeeding is not recommended.

Q8: What monitoring is required for patients receiving Ixabepilone?

A: Frequent complete blood counts (CBCs), liver function tests, and assessment for signs of neuropathy and hypersensitivity reactions are necessary.

Q9: What premedication is recommended before Ixabepilone infusion?

A: Patients should be premedicated with H1 and H2 antagonists (e.g., diphenhydramine and ranitidine) approximately 1 hour before infusion.

Q10: How is hepatic impairment managed in patients receiving Ixabepilone?

A: Dosage reductions are required for mild and moderate hepatic impairment. Ixabepilone is not recommended for severe hepatic dysfunction. In combination therapy with capecitabine, ixabepilone is contraindicated if AST/ALT>2.5x ULN or total bilirubin >1x ULN.