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Mechanism Of Action

Eribulin inhibits the growth phase of microtubules without affecting the shortening phase and sequesters tubulin into nonproductive aggregates. Eribulin exerts its effects via a tubulin-based antimitotic mechanism leading to G2/M cell-cycle block, disruption of mitotic spindles, and, ultimately, apoptotic cell death after prolonged mitotic blockage.

In addition, eribulin treatment of human breast cancer cells caused changes in morphology and gene expression as well as decreased migration and invasiveness in vitro. In mouse xenograft models of human breast cancer, eribulin treatment was associated with increased vascular perfusion and permeability in the tumor cores, resulting in reduced tumor hypoxia, and changes in the expression of genes in tumor specimens associated with a change in phenotype.


The pharmacokinetics (PK) of eribulin is linear with a mean elimination half-life of approximately 40 hours, a mean volume of distribution of 43 L/m² to 114 L/m² and mean clearance of 1.16 L/hr/m² to 2.42 L/hr/m² over the dose range of 0.25 mg/m² to 4.0 mg/m². The human plasma protein binding of eribulin at concentrations of 100 ng/mL to 1,000 ng/mL ranges from 49% to 65% Eribulin exposure after multiple dosing is comparable to that following a single dose. No accumulation of eribulin is observed with weekly administration.


Unchanged eribulin was the major circulating species in plasma following administration of 14C-eribulin to patients. Metabolite concentrations represented < 0.6% of parent compound, confirming that there are no major human metabolites of eribulin. Cytochrome P450 3A4 (CYP3A4) negligibly metabolizes eribulin in vitro.


Eribulin is eliminated primarily in feces unchanged. After administration of 14C-eribulin to patients, approximately 82% of the dose was eliminated in feces and 9% in urine. Unchanged eribulin accounted for approximately 88% and 91% of the dose in feces and urine, respectively.

Effects of Age, Gender, and Race

Based on a population pharmacokinetic analysis with data collected from 340 patients, gender, race, and age do not have a clinically meaningful effect on the PK of eribulin.

Drug Interactions

Effect of Other Drugs on HALAVEN

The effect of a strong CYP3A4 inhibitor and a P-gp inhibitor, ketoconazole, on the PK of eribulin was studied in a crossover trial of 12 patients with advanced solid tumors. No clinically relevant PK interaction was observed when HALAVEN was administered with or without ketoconazole (the geometric mean ratio of the AUC: 0.97; 90%CI: 0.83, 1.12).

The effect of a CYP3A4 inducer, rifampin, on the PK of eribulin was studied in a crossover trial of 14 patients with advanced solid tumors. No clinically relevant PK interaction was observed when HALAVEN was administered with or without rifampin (the geometric mean ratio of the AUC: 1.10; 90CI%: 0.91, 1.34).

Effect of HALAVEN on Other Drugs

Eribulin shows no induction potential for CYP1A, CYP2C9, CYP2C19, and CYP3A in primary human hepatocytes. Eribulin inhibits CYP3A4 activity in human liver microsomes, but it is unlikely that eribulin will substantially increase the plasma levels of CYP3A4 substrates. No significant inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP2E1 was detected with eribulin concentrations up to 5 μM in pooled human liver microsomes. In vitro drug interaction studies indicate that eribulin does not inhibit drugs that are substrates of these enzymes and it is unlikely that eribulin will affect plasma levels of drugs that are substrates of CYP enzymes. Eribulin is a substrate and a weak inhibitor of the drug efflux transporter P-gp in vitro.

Specific Populations

Hepatic Impairment

A study evaluated the PK of eribulin in patients with mild (Child-Pugh A; n=7) and moderate (Child-Pugh B; n=5) hepatic impairment. Compared to patients with normal hepatic function (n=6), eribulin exposures increased 1.8-fold and 2.5-fold in patients with mild and moderate hepatic impairment, respectively. Administration of HALAVEN at a dose of 1.1 mg/m² to patients with mild hepatic impairment and 0.7 mg/m² to patients with moderate hepatic impairment resulted in similar exposure to eribulin as a dose of 1.4 mg/m² to patients with normal hepatic function [see DOSAGE AND ADMINISTRATION, Use in Specific Populations].

Renal Impairment

A study evaluated the PK of eribulin in patients with moderate (CrCl: 30-49 mL/min; n=7) and severe (CrCl: 15-29 mL/min; n=6) renal impairment. Compared to patients with normal renal function (CrCl ≥ 80 mL/min; n=6), patients with moderate and severe renal impairment have 1.5-fold higher eribulin dosenormalized exposures. However for patients with mild renal impairment the data indicate no dose adjustment is necessary [see DOSAGE AND ADMINISTRATION, Use in Specific Populations].

Cardiac Electrophysiology

The effect of HALAVEN on the QTc interval was assessed in an open-label, uncontrolled, multicenter, single-arm dedicated QT trial. A total of 26 patients with solid tumors received 1.4 mg/m² of HALAVEN on Days 1 and 8 of a 21-day cycle. A delayed QTc prolongation was observed on Day 8, with no prolongation observed on Day 1. The maximum mean QTcF change from baseline (95% upper confidence interval) was 11.4 (19.5) ms.

Clinical Studies

Study 1 was an open-label, randomized, multicenter trial of 762 patients with metastatic breast cancer who received at least two chemotherapeutic regimens for the treatment of metastatic disease and experienced disease progression within 6 months of their last chemotherapeutic regimen. Patients were required to receive prior anthracycline- and taxane- based chemotherapy for adjuvant or metastatic disease. Patients were randomized (2:1) to receive HALAVEN (n=508) or a single agent therapy selected prior to randomization (control arm, n=254). Randomization was stratified by geographic region, HER2/neu status, and prior capecitabine exposure. HALAVEN was administered at a dose of 1.4 mg/m² on Days 1 and 8 of a 21-day cycle. HALAVEN-treated patients received a median of 5 cycles (range: 1 to 23 cycles) of therapy. Control arm therapy consisted of 97% chemotherapy (26% vinorelbine, 18% gemcitabine, 18% capecitabine, 16% taxane, 9% anthracycline, 10% other chemotherapy), and 3% hormonal therapy. The main efficacy outcome was overall survival.

Patient demographic and baseline characteristics were comparable between the treatment arms. The median age was 55 (range: 27 to 85 years) and 92% were White. Sixty-four percent of patients were enrolled in North America/Western Europe/Australia, 25% in Eastern Europe/Russia, and 11% in Latin America/South Africa. Ninety-one percent of patients had a baseline ECOG performance status of 0 or 1. Tumor prognostic characteristics, including estrogen receptor status (positive: 67%, negative: 28%), progesterone receptor status (positive: 49%, negative: 39%), HER2/neu receptor status (positive: 16%, negative: 74%), triple negative status (ER-, PR-, HER2/neu-: 19%), presence of visceral disease (82%, including 60% liver and 38% lung) and bone disease (61%), and number of sites of metastases (greater than two: 50%), were also similar in the HALAVEN and control arms. Patients received a median of four prior chemotherapy regimens in both arms.

In Study 1, a statistically significant improvement in overall survival was observed in patients randomized to the HALAVEN arm compared to the control arm (see Table 3). An updated, unplanned survival analysis, conducted when 77% of events had been observed (see Figure 1), was consistent with the primary analysis. In patients randomized to HALAVEN, the objective response rate by the RECIST criteria was 11% (95% CI: 8.6%, 14.3%) and the median response duration was 4.2 months (95% CI: 3.8, 5.0 months).

Table 3 : Comparison of Overall Survival in HALAVEN and Control Arm - Study 1

Overall Survival HALAVEN
Control Arm
Primary survival analysis
  Number of deaths 274 148
  Median, months (95% CI) 13.1 (11.8, 14.3) 10.6 (9.3, 12.5)
  Hazard Ratio (95% CI)a 0.81 (0.66, 0.99)
  P valueb 0.041
Updated survival analysis
  Number of deaths 386 203
  Median, months (95% CI) 13.2 (12.1, 14.4) 10.6 (9.2, 12.0)
CI = confidence interval
a Based on Cox proportional hazards model stratified by geographic region, HER2 status, and prior capecitabine therapy.
b Based on a log-rank test stratified by geographic region, HER2 status, and prior capecitabine therapy.

Figure 1 : Updated Overall Survival Analysis for Study 1

Updated Overall Survival Analysis - Illustration

Last reviewed on RxList: 1/15/2016
This monograph has been modified to include the generic and brand name in many instances.

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