Epothilones

FDA-Approved Drugs: Ixabepilone (Ixempra, BMS 247550)
Investigational Drugs: Patupilone (EPO906)

Indications
Ixabepilone is indicated in combination with capecitabine (Xeloda) for the treatment of patients with metastatic or locally advanced breast cancer resistant to prior anthracycline and paclitaxel treatment (or for whom this treatment is contraindicated). Anthracycline resistance is defi ned as progression within 6 months of adjuvant therapy or 3 months of treatment for metastatic breast cancer; paclitaxel resistance is defi ned as progression on therapy or within 12 months of adjuvant therapy, or 4 months of treatment for metastatic breast cancer.

Mechanism of Action
Epothilones are a new class of antineoplastic agents which cause tubulin polymerization and stabilization, similar to paclitaxel. Epothilones are more soluble in water, however, so they do not require a solubilizing agent such as Cremaphor. There are three classes: epothilone A, B, and D. Ixabepilone (Ixempra) is a semisynthetic analog of epothilone B, and it binds to β-tubulin subunits on microtubules to suppress the changes of the microtubules during mitosis. Thus the cancer cell is unable to complete cell division, and it dies. In addition, ixabepilone has low susceptibility to tumor resistance mechanisms. This group of drugs is thought to have activity in tumor cell lines that are resistant to paclitaxel due to mutations in β-tubulin.

Ixabepilone Metabolism
Ixabepilone is extensively metabolized in the liver via the CYP3A4 microenzyme system, forming at least 30 nonactive metabolites, which are then excreted within 7 days into the urine (21% of the dose) and feces (65%). Ixabepilone has a terminal half-life of 52 hours.

Off Label Uses or Other Uses
None known.

Patient Education
Teach the patient the following:

• The drug is given once every 3 weeks together with capecitabine (a pill taken twice daily for 14 days, then following a break for 7 days is repeated every 3 weeks).
• Blood tests will be drawn to evaluate liver function, as the drug should not be taken if the patient has liver problems.
• Blood tests also will be drawn to evaluate neutrophil and platelet counts, to make sure the counts are high enough to protect the body from infection and bleeding.
• Patient should report any dizziness or difficulty thinking during drug administration, as the drug diluent contains alcohol.
• Patient should avoid crowds and report any fever, chills, or signs and symptoms of infection or bleeding right away. • Patient should use effective contraception to prevent pregnancy during therapy.
• Allergic reactions may occur during the infusion, so patient should tell the nurse right away if patient notices itching, flushing, difficulty breathing, feels dizzy or faint, or experiences anything different from usual.
• Patient should report any numbness / tingling of the fingertips and toes and any difficulty with activities of daily living.
• Patient should rinse the mouth after meals and at bedtime, and should report any pain or difficulty with eating or drinking.
• Patient should not drink grapefruit juice or take St. John’s Wort, as they may affect the drug dose.

Interactions Strong CYP3A4 inhibitors may prevent metabolism of ixabepilone, thereby causing increased serum concentrations of ixabepilone; these drugs must be avoided, or the ixabepilone dose should be reduced to 20 mg/m2 if they mustbe coadministered. CYP3A4 inhibitors include ketoconazole, itraconazole, clarithromycin, tazanavir, nefazodone, saquinavir, telithromycin, ritonavir, amprenavir, indinavir, nelfinavir, delavirdine, or voriconazole; and grapefruit juice. If a reduced dose is used, then the CYP3A4 inhibitor is discontinued, wait 1 week before increasing the dose (washout period).

Strong CYP3A4 inducers may increase the metabolism of ixabepilone, thus reducing the serum level. These drugs should be avoided (dexamethasone, phenytoin, carbamazepine, rifampin, rifampicin, rifabutin, phenobarbital, St. John’s Wort).

When ixabepilone is given with capecitabine, there is an interaction resulting in a decreased ixabepilone serum level (by 19%) while the capecitabine serum level is decreased by 27%; 5-FU level is increased by 14% as compared to serum levels when ixabepilone and capecitabine are given separately.

Special Considerations
• Patients should be premedicated with H1 and H2 antagonists (eg, diphenhydramine at 50 mg PO, and ranitidine at 150 mg PO) 1 hour prior to drug administration.
• Assess patient’s cognitive status during drug administration as drug diluent contains dehydrated alcohol (USP).
• Monitor for hypersensitivity reactions, and stop drug if a hypersensitivity reaction is suspected (eg, fl ushing, rash, dyspnea, bronchospasm). Notify physician/nurse practitioner/physician assistant, and administer supportive treatment as needed (eg, epinephrine, corticosteroids).
If reaction resolves, in subsequent cycles administer a corticosteroid in addition to the usual premedication, and extend infusion time.

Contraindications/Precautions
Ixabepilone together with capecitabine is contraindicated in patients with hepatic dysfunction (AST or ALT > 2.5 × upper limit of normal [ULN] or bilirubin > 1 × ULN) as there is increased risk of neutropenia-related death, and of other grade 3–4 toxicity. Drug is also contraindicated in patients with hypersensitivity to Cremaphor EL or polyoxyethylated castor oil (eg, prior paclitaxel), and patients with a baseline neutrophil count < 1,500 cells/mm3 or a platelet count < 100,000 cells/mm3.

Adverse Reactions to Ixabepilone, by SystemCV: Rare cardiac ischemia, superventricular arrhythmia, ventricular dysfunction, myocardial infarction, angina pectoris, hypotension, embolism
EENT: none
GI: Nausea, vomiting, stomatitis, mucositis, diarrhea, anorexia,* abdominal pain,* constipation,* rare ileus, colitis, dysphagia, acute hepatic failure
GU: Urinary tract infection, rare nephrolithiasis, renal failure
Hematologic: Leukopenia, anemia, neutropenia, thrombocytopenia, rare coagulopathy
Metabolic: Musculoskeletal: Arthralgias, myalgias, pain, palmar-plantar erythrodysesthesia (hand-foot syndrome),* muscle weakness, spasm, trismus
Neurological: Peripheral sensory neuropathy, cognitive impairment (from dehydrated alcohol USP in diluent), syncope, lethargy
Respiratory: Respiratory tract infection, rare pneumonitis, hypoxia
Skin: Alopecia, nail disorders,* rare erythema multiforme
Other: Hypersensitivity reaction, fatigue, chills

*In combination with capecitabine