Ixabepilone (Ixempra)

Semisynthetic epothilone.

Promotes cell death by stabilizing microtubules and induction of apoptosis.

Less susceptible than taxanes (which stabilize microtubules) to multiple drug resistant mechanisms.

Demonstrates low susceptibility to mechanisms of tumor resistance including the over expression of efflux transporters and class III isoform of beta-tubulin.

Binds to beta-tubulin to stabilize microtubule polymers, leading to cell cycle arrest at the G2/M phase and to apoptosis.

Binds to a different site on Beta-tubulin than the taxanes.

Retains activity against malignancies that are refractive to taxanes and to those that develop resistance to them.

Minimally affected by P-glycoprotein, which is responsible for conferring resistance to taxanes, anthracycline, and vinca alkaloids.

Metabolized by the CYP system and may be susceptible to drug interactions.

With impaired hepatic function dose reduction may be needed.

Formulation contains 40% alcohol, and Cremophor EL.

Toxicities include alopecia, mild to moderate sensory neuropathy which is mostly reversible and neutropenia.

Adverse reactions similar to taxanes and are schedule dependent with more neurotoxicity with shorter infusions.

Toxicities include fatigue, asthenia, myalgias, arthralgias and alopecia.

Increased neurotoxicity in patients with preexisting neuropathy.

Phase II of 65 women with prior anthracycline adjuvant therapy treatment received agent 40 mg/m2 by 3 hour IV infusion every three weeks as first line management for metastatic disease: objective response rate of 41.5% with 35.4% having stable disease and median time to tumor response of 6 weeks, median time to progressive disease 4.8 months, median duration of response of 8.2 months and a median survival of 22 months.

In a randomized trial of ixabepilone with capecitabine compared to capecitabine alone in patients with advanced breast cancer, anthracycline and taxane resistant disease: the addition to capecitabine increased progression free survival with a 25% reduction in the estimated risk for disease progression compared with monotherapy, the median progression free survival prolonged to 5.8 months compared to 4.2 months with capecitabine alone (Thomas).

Overall response rate of 57%, as monotherapy in breast cancer.

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