Pharmacy & Therapeutics - September 2008 - (Page 524)

DRUG FORECAST ef ficacy of taxanes. 22–25 Various point mutations in beta-III tubulin may also confer resistance to taxanes but not to epothilones. 23 In addition, P-gp over expression does not affect the cytotoxicity of epothilones to the same degree as it af fects other chemotherapeutic agents.26 A novel microtubule-stabilizing agent, ixabepilone, was developed to optimize the properties of naturally occurring epothilone B (Figure 1).19,21,23,27 Of the epothilones currently in development, ixabepilone is the most clinically advanced.21 Ixabepilone (Ixempra) Epothilone B Figure 1 Chemical structures of ixabepilone and epothilone B. In epothilone B, an oxygen atom is in the macrolide ring; in ixabepilone, that O atom is replaced with a nitrogen atom. once-every-three-week regimen.29–31 In total, 63 patients with a range of solid tumors were treated according to this schedule at dose levels ranging from 7.4 to 65 mg/m2. Responses to therapy were obser ved in patients with melanoma, non–small-cell lung cancer, ovarian cancer, and breast cancers (taxane-naive and taxane-refractor y). Dose-limiting toxicities included grade 4 neutropenia, peripheral neuropathy, gastrointestinal (GI) discomfort, fatigue, and emesis. Of note, the incidence of neuropathy in these trials was theorized to be related to peak concentrations; therefore, a threehour instead of a one-hour infusion schedule was recommended for phase 2 studies.31 For phase 2 development of this schedule, 40 mg/m2 was established as the recommended dose of ixabepilone. Phase 1 studies have also established the maximum tolerated dose for ixabepilone when administered as a one-hour daily infusion on three or five consecutive days ever y three weeks.28,32 On these schedules, the maximum tolerated dose was 6 or 8 mg/m2 per day.28,32 Weekly schedules of ixabepilone have also been investigated.33–35 activity was obser ved against anthracycline-resistant, taxane-resistant, and capecitabine-resistant tumors. The primary outcome measure for these studies was the ORR. ORRs ranged from 11.5% to 57% and were dependent on previous therapy and the line of therapy.36–41 As neoadjuvant therapy, ixabepilone appears to compare favorably in activity with that of other cytotoxic monotherapies.41 Data have been reported from a phase 2 trial in 164 patients with locally advanced breast cancer. Up to four cycles of ixabepilone (40 mg/m2 infused over three hours every three weeks) were administered as primary systemic (neoadjuvant) therapy to patients with invasive breast cancer (stages IIA–IIIB) before surgery. A pathological complete response (pCR) rate of 18% (29/161) was observed, and 17 of these patients (11%) also achieved pCRs in the axillary lymph nodes. The pCR rate in patients with triple-negative (estrogen receptor/ progesterone receptor/human epidermal growth factor receptor-2 [ER/PR/ HER2–negative]) tumors was 26% (11/42).41 As a first-line therapy, ixabepilone was evaluated in 65 patients with metastatic breast cancer who had received one (92%) or two (8%) prior anthracyclinebased adjuvant regimens.39 In this single-arm, phase 2 study, ixabepilone monotherapy was given as a 40- or 50mg/m2 infusion over one or three hours every three weeks. Patients who had received a taxane as part of their anthracycline-based adjuvant regimen were not excluded from the study, provided that more than one year had elapsed since the completion of their treatment. However, most patients (83%) had not received a taxane previously. The ORR was 41.5% (95% confidence inter val [CI], 29.4%–54.4%) with a median duration of PHARMACOKINETICS In patients with cancer, the pharmacokinetic properties of ixabepilone are linear at doses of 15 to 57 mg/m2.18 The drug disposition of ixabepilone is characterized by a rapid distributive phase, followed by a more prolonged terminal elimination phase.28,29 Ixabepilone has a terminal elimination half-life of approximately 52 hours.18 At the recommended dose and schedule (40 mg/m2 administered intravenously over three hours every three weeks), no accumulation of ixabepilone within the plasma is expected, because the cycle length is approximately 10 times the terminal elimination half-life.18 Ixabepilone is typically distributed across a large volume at steady state (in excess of 1,000 L). This is consistent with extensive tissue uptake and high binding (range, 67%–77%) to serum proteins.18 Ixabepilone is extensively metabolized in the liver by oxidative metabolism via cytochrome P450 (CYP 3A4) to more than 30 metabolites, none of which has been shown to have clinically relevant cytotoxic activity.18 Elimination occurs primarily via the liver. After an intravenous (IV) dose of 14[C]-ixabepilone was administered to patients, 65% of the dose was eliminated in the feces and 21% of the dose was excreted in the urine.18 Phase 2 Clinical Studies The clinical efficacy of ixabepilone as a single agent has been studied for a variety of tumor types and has been extensively evaluated in phase 2 trials of both advanced and metastatic breast cancer (Table 1).36–41 In these studies, ixabepilone has demonstrated promising clinical activity and good tolerability across a broad spectrum of patients. In addition, given the significant negative impact that drug resistance may have on outcome, it is particularly encouraging to note that in these trials, ixabepilone CLINICAL TRIALS Phase 1 Clinical Studies In the phase 1 setting, a number of IV infusion schedules of ixabepilone have been evaluated. These include a single dose every three weeks, a daily dose for three or five days every three weeks, and a weekly schedule. Several authors have investigated the 524 P&T® • September 2008 • Vol. 33 No. 9

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Pharmacy & Therapeutics - September 2008 Contents Editorial Medication Errors Prescription: Washington New Drugs/Drug News/New Medical Devices Drug Forecast Effect of Prescription Copays on Adherence and Treatment Failure with Oral Antidiabetic Medications Vaccine Declinations Present New Challenges for Public Health Universal Health Care in America Digestive Disease Week and American Diabetes Association Pharmaceutical Approval Update

Pharmacy & Therapeutics - September 2008

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