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Mechanism of Action
Ixabepilone is a semi-synthetic analog of epothilone B. Ixabepilone binds directly to β-tubulin subunits on microtubules, leading to suppression of microtubule dynamics. Ixabepilone suppresses the dynamic instability of αβ-II and αβ-III microtubules. Ixabepilone possesses low in vitro susceptibility to multiple tumor resistance mechanisms including efflux transporters, such as MRP-1 and P-glycoprotein (P-gp). Ixabepilone blocks cells in the mitotic phase of the cell division cycle, leading to cell death.
In cancer patients, ixabepilone has a plasma concentration-dependent effect on tubulin dynamics in peripheral blood mononuclear cells that is observed as the formation of microtubule bundles. Ixabepilone has antitumor activity in vivo against multiple human tumor xenografts, including drug-resistant types that overexpress P-gp, MRP-1, and βIII tubulin isoforms, or harbor tubulin mutations. Ixabepilone is active in xenografts that are resistant to multiple agents including taxanes, anthracyclines, and vinca alkaloids. Ixabepilone demonstrated synergistic antitumor activity in combination with capecitabine in vivo. In addition to direct antitumor activity, ixabepilone has antiangiogenic activity.
Following administration of a single 40 mg/m² dose of IXEMPRA in patients with cancer, the mean Cmax was 252 ng/mL (coefficient of variation, CV 56%) and the mean AUC was 2143 ng•hr/mL (CV 48%). Typically, Cmax occurred at the end of the 3 hour infusion. In cancer patients, the pharmacokinetics of ixabepilone were linear at doses of 15 to 57 mg/m².
The mean volume of distribution of 40 mg/m² ixabepilone at steady-state was in excess of 1000 L. In vitro, the binding of ixabepilone to human serum proteins ranged from 67 to 77%, and the blood-to-plasma concentration ratios in human blood ranged from 0.65 to 0.85 over a concentration range of 50 to 5000 ng/mL.
Ixabepilone is extensively metabolized in the liver. In vitro studies indicated that the main route of oxidative metabolism of ixabepilone is via CYP3A4. More than 30 metabolites of ixabepilone are excreted into human urine and feces. No single metabolite accounted for more than 6% of the administered dose. The biotransformation products generated from ixabepilone by human liver microsomes were not active when tested for in vitro cytotoxicity against a human tumor cell line.
In vitro studies using human liver microsomes indicate that clinically relevant concentrations of ixabepilone do not inhibit CYP3A4, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. Ixabepilone does not induce the activity or the corresponding mRNA levels of CYP1A2, CYP2B6, CYP2C9, or CYP3A4 in cultured human hepatocytes at clinically relevant concentrations. Therefore, it is unlikely that ixabepilone will affect the plasma levels of drugs that are substrates of CYP enzymes.
Ixabepilone is eliminated primarily as metabolized drug. After an intravenous 14[C]-ixabepilone dose to patients, approximately 86% of the dose was eliminated within 7 days in feces (65% of the dose) and in urine (21% of the dose). Unchanged ixabepilone accounted for approximately 1.6% and 5.6% of the dose in feces and urine, respectively. Ixabepilone has a terminal elimination half-life of approximately 52 hours. No accumulation in plasma is expected for ixabepilone administered every 3 weeks.
Drug Transport Systems
Ixabepilone is a substrate and a weak inhibitor for the drug efflux transporter P-glycoprotein (P-gp) in vitro .
Ixabepilone is not a substrate for the breast cancer resistance protein (BCRP) in vitro .
Effects of Age, Gender, and Race
Based upon a population pharmacokinetic analysis in 676 cancer patients, gender, race, and age do not have meaningful effects on the pharmacokinetics of ixabepilone.
Effect of Ixabepilone on QT/QTc Interval
The QT prolongation potential of ixabepilone was assessed as part of an uncontrolled, open-label, single-dose study in advanced cancer patients. Fourteen patients received a single dose of IXEMPRA 40 mg/m² intravenously over 3 hours and serial ECGs were collected over 24 hours. The maximum mean ΔQTcF was observed 1 hour after the end of infusion and was 8 ms (upper 95% CI: 12 ms). No patients had a QTcF interval > 450 ms or ΔQTcF > 30 ms after IXEMPRA administration. However, small increases in QTc interval with the use of ixabepilone cannot be excluded due to study design limitations.
In rats, single intravenous doses of ixabepilone from 60 to 180 mg/m² (mean AUC values ≥ 8156 ng•h/mL) were associated with mortality occurring between 5 and 14 days after dosing, and toxicity was principally manifested in the gastrointestinal, hematopoietic (bone-marrow), lymphatic, peripheral-nervous, and male-reproductive systems. In dogs, a single intravenous dose of 100 mg/m² (mean AUC value of 6925 ng•h/mL) was markedly toxic, inducing severe gastrointestinal toxicity and death 3 days after dosing.
In an open-label, multicenter, multinational, randomized trial of 752 patients with metastatic or locally advanced breast cancer, the efficacy and safety of IXEMPRA (40 mg/m² every 3 weeks) in combination with capecitabine (at 1000 mg/m² twice daily for 2 weeks followed by 1 week rest) were assessed in comparison with capecitabine as monotherapy (at 1250 mg/m² twice daily for 2 weeks followed by 1 week rest). Patients were previously treated with anthracyclines and taxanes. Patients were required to have demonstrated tumor progression or resistance to taxanes and anthracyclines as follows:
- tumor progression within 3 months of the last anthracycline dose in the metastatic setting or recurrence within 6 months in the adjuvant or neoadjuvant setting, and
- tumor progression within 4 months of the last taxane dose in the metastatic setting or recurrence within 12 months in the adjuvant or neoadjuvant setting.
For anthracyclines, patients who received a minimum cumulative dose of 240 mg/m² of doxorubicin or 360 mg/m² of epirubicin were also eligible.
Sixty-seven percent of patients were White, 23% were Asian, and 3% were Black. Both arms were evenly matched with regards to race, age (median 53 years), baseline performance status (Karnofsky 70-100%), and receipt of prior adjuvant or neo-adjuvant chemotherapy (75%). Tumors were ER-positive in 47% of patients, ER-negative in 43%, HER2-positive in 15%, HER2-negative in 61%, and ER-negative, PR-negative, HER2negative in 25%. The baseline disease characteristics and previous therapies for all patients (n=752) are shown in Table 6.
Table 6: Baseline Disease Characteristics and Previous Therapies
|IXEMPRA with capecitabine n=375||Capecitabine n=377|
|Site of disease|
|Visceral disease (liver or lung)||316 (84%)||315 (84%)|
|Liver||245 (65%)||228 (61%)|
|Lung||180 (48%)||174 (46%)|
|Lymph node||250 (67%)||249 (66%)|
|Bone||168 (45%)||162 (43%)|
|Skin/soft tissue||60 (16%)||62 (16%)|
|Number of prior chemotherapy regimens in metastatic settinga|
|0||27 ( 7%)||33 ( 9%)|
|1||179 (48%)||184 (49%)|
|2||152 (41%)||138 (37%)|
|≥ 3||17 ( 5%)||22 ( 6%)|
|Anthracycline resistanceb||164 (44%)||165 (44%)|
|Neoadjuvant/adjuvant setting||40 (11%)||44 (12%)|
|Metastatic setting||327 (87%)||319 (85%)|
| a For IXEMPRA plus capecitabine
versus capecitabine only, prior treatment in the metastatic setting included
cyclophosphamide (25% vs. 23%), fluorouracil (22% vs. 16%), vinorelbine
(11% vs. 12%), gemcitabine (9% each arm), carboplatin (9% vs. 7%), liposomal
doxorubicin (3% each arm), and cisplatin (2% vs. 3%).
b Tumor progression within 3 months in the metastatic setting or recurrence within 6 months in the adjuvant or neoadjuvant setting.
c 24% and 21% of patients had received 2 or more taxane-containing regimens in the combination and single agent treatment groups, respectively.
The patients in the combination treatment group received a median of 5 cycles of treatment and patients in the capecitabine monotherapy treatment group received a median of 4 cycles of treatment.
The primary endpoint of the study was progression-free survival (PFS) defined as time from randomization to radiologic progression as determined by Independent Radiologic Review (IRR), clinical progression of measurable skin lesions or death from any cause. Other study endpoints included objective tumor response based on Response Evaluation Criteria in Solid Tumors (RECIST), time to response, response duration, and overall survival.
IXEMPRA in combination with capecitabine resulted in a statistically significant improvement in PFS compared to capecitabine. The results of the study are presented in Table 7 and Figure 1.
Table 7: Efficacy of IXEMPRA in Combination with Capecitabine
vs Capecitabine Alone – Intent-to-Treat Analysis
|Efficacy Parameter||IXEMPRA with capecitabine n=375||Capecitabine n=377|
|Number of eventsa||242||256|
|Median (95% CI)||5.7 months (4.8 - 6.7)||4.1 months (3.1 - 4.3)|
|Hazard Ratiob (95% CI)||0.69 (0.58 - 0.83)|
|p-valuec (Log rank)||< 0.0001|
|Objective Tumor Response Rate (95% CI)||34.7% (29.9 - 39.7)||14.3% (10.9 - 18.3)|
|p-valuec (CMH)d||< 0.0001|
|Duration of Response, Median (95% CI)||6.4 months (5.6 - 7.1)||5.6 months (4.2 - 7.5)|
|a Patients were censored for
PFS at the last date of tumor assessment prior to the start of subsequent
therapy. In patients where independent review was not available PFS was
censored at the randomization date.
b For the hazard ratio, a value less than 1.00 favors combination treatment.
c Stratified by visceral metastasis in liver/lung, prior chemotherapy in metastatic setting, and anthracycline resistance.
d Cochran-Mantel-Haenszel test
Figure 1: Progression-free Survival Kaplan Meier Curves
There was no statistically significant difference in overall survival between treatment arms in this study, as well as in a second similar study. In the study described above, the median overall survivals were 12.9 months (95% CI: 11.5, 14.2) in the combination therapy arm and 11.1 months (95% CI: 10.0, 12.5) in the capecitabine alone arm [Hazard Ratio 0.90 (95% CI: 0.77, 1.05), p-value=0.19].
In the second trial, comparing IXEMPRA in combination with capecitabine versus capecitabine alone, conducted in 1221 patients pretreated with an anthracycline and taxane, the median overall survivals were 16.4 months (95% CI: 15.0, 17.9) in the combination therapy arm and 15.6 months (95% CI: 13.9, 17.0), in the capecitabine alone arm [Hazard Ratio 0.90 (95% CI: 0.78, 1.03), p-value=0.12].
IXEMPRA was evaluated as a single agent in a multicenter single-arm study in 126 women with metastatic or locally advanced breast cancer. The study enrolled patients whose tumors had recurred or had progressed following two or more chemotherapy regimens including an anthracycline, a taxane, and capecitabine. Patients who had received a minimum cumulative dose of 240 mg/m² of doxorubicin or 360 mg/m² of epirubicin were also eligible. Tumor progression or recurrence were prospectively defined as follows:
- Disease progression while on therapy in the metastatic setting (defined as progression while on treatment or within 8 weeks of last dose),
- Recurrence within 6 months of the last dose in the adjuvant or neoadjuvant setting (only for anthracycline and taxane),
- HER2-positive patients must also have progressed during or after discontinuation of trastuzumab.
In this study, the median age was 51 years (range, 30-78), and 79% were White, 5% Black, and 2% Asian, Karnofsky performance status was 70-100%, 88% had received two or more prior chemotherapy regimens for metastatic disease, and 86% had liver and/or lung metastases. Tumors were ER-positive in 48% of patients, ER-negative in 44%, HER2-positive in 7%, HER2-negative in 72%, and ER-negative, PR-negative, HER2-negative in 33%.
IXEMPRA was administered at a dose of 40 mg/m² intravenously over 3 hours every 3 weeks. Patients received a median of 4 cycles (range 1 to 18) of IXEMPRA therapy.
Objective tumor response was determined by independent radiologic and investigator review using RECIST. Efficacy results are presented in Table 8.
Table 8: Efficacy of IXEMPRA in Metastatic and Locally Advanced
|Objective tumor response rate (95% CI)|
|IRR Assessmenta (n=113)||12.4% (6.9 - 19.9)|
|Investigator Assessment (n=126)||18.3% (11.9 - 26.1)|
|Time to responseb (n=14)|
|Median, weeks (min - max)||6.1 (5 - 54.4)|
|Duration of responseb(n=14)|
|Median, months (95% CI)||6.0 (5.0 - 7.6)|
|a All responses were partial.
b As assessed by IRR.
Last reviewed on RxList: 10/27/2011
This monograph has been modified to include the generic and brand name in many instances.
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