Eribulin (Halaven®): A Comprehensive Monograph on a Novel Microtubule Dynamics Inhibitor for Advanced Malignancies

1.0 Executive Summary

Eribulin is a potent antineoplastic agent belonging to the halichondrin class of microtubule dynamics inhibitors. It is a fully synthetic, structurally simplified analogue of halichondrin B, a complex natural product originally isolated from the marine sponge Halichondria okadai.[1] Marketed under the brand names Halaven® and Mevlyq®, eribulin represents a significant achievement in medicinal chemistry, translating a rare and complex natural lead into a viable therapeutic drug.[2]

The primary mechanism of action is unique among microtubule-targeting agents. Eribulin binds to high-affinity sites at the positive (+) ends of β-tubulin, inhibiting the growth phase (polymerization) of microtubules while leaving the shortening phase (depolymerization) unaffected.[2] This "end-poisoning" mechanism sequesters tubulin into non-productive aggregates, leading to the disruption of mitotic spindles, an irreversible G2/M cell-cycle blockade, and subsequent apoptosis.[1] In addition to these cytotoxic effects, eribulin exerts non-mitotic actions on the tumor microenvironment, including vascular remodeling to improve tumor perfusion and phenotypic changes consistent with the reversal of epithelial-mesenchymal transition (EMT), which may contribute to its observed survival benefits.[2]

Clinically, eribulin is approved for the treatment of patients with metastatic breast cancer (mBC) who have been heavily pre-treated, specifically after receiving at least two prior chemotherapeutic regimens, including an anthracycline and a taxane.[4] It is also approved for adult patients with unresectable or metastatic liposarcoma who have received a prior anthracycline-containing regimen.[1] Its approval in these settings was based on pivotal Phase III trials that demonstrated a statistically significant improvement in overall survival (OS).[9]

Administered intravenously, eribulin exhibits linear pharmacokinetics with a long terminal half-life of approximately 40 hours.[4] A key feature is its minimal metabolism by the cytochrome P450 system, particularly CYP3A4, and its primary elimination as an unchanged drug in the feces.[4] This profile suggests a low potential for pharmacokinetic drug-drug interactions but necessitates dose adjustments in patients with hepatic or moderate-to-severe renal impairment.[7]

The safety profile of eribulin is characterized by several clinically significant adverse reactions. The most common and dose-limiting toxicities are myelosuppression, particularly neutropenia, and peripheral neuropathy, which was the leading cause of treatment discontinuation in clinical trials.[2] Other frequent side effects include fatigue, alopecia, nausea, and constipation.[2] Eribulin also carries a risk of prolonging the QTc interval, requiring caution and monitoring, especially when co-administered with other QTc-prolonging agents.[2]

2.0 Introduction: A Marine-Derived Antineoplastic Agent

2.1 Discovery and Developmental Trajectory: From Sea Sponge to Syringe

The development of eribulin is a compelling narrative of scientific perseverance, bridging the fields of marine biology, natural product chemistry, and pharmaceutical innovation. The story begins with the exploration of the ocean's vast chemical diversity, which has yielded numerous compounds with therapeutic potential.[17]

2.1.1 The Natural Product Precursor: Halichondrin B

In 1985 and 1986, Japanese chemists Daisuke Uemura and Yoshimasa Hirata isolated a structurally complex polyether macrolide from the marine sponge Halichondria okadai.[3] This compound, named halichondrin B, demonstrated extraordinary potency against cancer cells in preclinical models.[3] Its discovery generated immense excitement within the oncology research community and the National Cancer Institute, which subsequently funded efforts to harvest these marine sponges for further investigation.[3]

2.1.2 The Supply Problem and the Synthetic Challenge

A formidable obstacle quickly emerged, threatening to halt the development of halichondrin B: the problem of supply. The natural abundance of the compound was exceedingly low; for instance, harvesting one metric ton of sea sponge yielded a mere 300 mg of halichondrin B.[19] This scarcity made it impossible to source sufficient material for extensive clinical trials, let alone for commercial-scale production. The only viable path forward was to recreate this intricate molecule in the laboratory through total chemical synthesis. This was a monumental challenge, as halichondrin B is a molecular behemoth with a 54-carbon backbone and 32 distinct stereogenic centers, demanding precise three-dimensional control at every step of the synthesis.[18]

2.1.3 The Breakthrough in Synthetic Chemistry and the Genesis of Eribulin

The synthetic puzzle was solved in 1992 by a team led by Dr. Yoshito Kishi at Harvard University, who reported the first total synthesis of halichondrin B.[18] This landmark achievement in organic chemistry not only proved that such a complex molecule could be constructed from simple starting materials but also opened the door to creating structural analogues. Working in collaboration with the Eisai Research Institute, where Dr. Kishi served as a scientific advisor, the team began to explore which parts of the molecule were essential for its anticancer activity.[3]

Screening of a key intermediate from the Kishi synthesis, which contained only the C1-C38 macrolide portion of the molecule, revealed that this fragment retained the potent bioactivity of the parent compound.[18] This discovery was pivotal, as it allowed chemists at Eisai to focus on creating a range of structurally simplified analogues based on this active core. After synthesizing and testing over 180 variations, they identified a C35 primary amine-substituted compound as the most promising candidate.[22] This new molecule, designated E7389 (and later named eribulin), preserved the potent anticancer activity of halichondrin B but possessed greater chemical stability and a more favorable preclinical profile.[3] The term "structurally simplified" belies the immense complexity that remains; the final manufacturing process for Halaven®, the commercial formulation of eribulin, requires an extraordinary 62 distinct chemical transformations.[18] This journey from natural discovery to a synthetically accessible, clinically viable drug is a testament to the power of medicinal chemistry to overcome the limitations of nature.

2.1.4 Regulatory Milestones

Following extensive preclinical and clinical investigation, eribulin mesylate received priority review status from the U.S. Food and Drug Administration (FDA).[11] The FDA granted its first approval on November 15, 2010, for the treatment of metastatic breast cancer.[2] This was followed by approval from the European Medicines Agency (EMA) in March 2011 and Health Canada in December 2011.[2] Recognizing its efficacy in another area of unmet need, the FDA expanded eribulin's indication on January 28, 2016, to include the treatment of unresectable or metastatic liposarcoma.[10] Today, eribulin is approved in numerous countries worldwide and is also available as a generic medication.[2]

2.2 Chemical Identity and Physicochemical Properties

Eribulin is classified as a small molecule, synthetic organic compound.[4] Its intricate structure defines it as a macrocycle, a polyether, a polycyclic ether, a cyclic ketone, a primary amino compound, and a cyclic ketal.[1] For clinical and research purposes, it is crucial to distinguish between the active free base and the commercially available mesylate salt form.

The use of a salt form is a common and critical pharmaceutical strategy. The free base form of many drugs, including eribulin, often has poor solubility in aqueous solutions, making it unsuitable for intravenous formulation.[27] By reacting the basic primary amine group on the eribulin molecule with methanesulfonic acid, the more soluble and stable eribulin mesylate salt is formed.[28] This enhancement in physicochemical properties is what enables its formulation as a sterile injectable solution for clinical use. Consequently, all clinical dosing is based on the mass of the mesylate salt, not the free base. For example, the standard dose of 1.4 mg/m² refers to eribulin mesylate, which is equivalent to 1.23 mg/m² of the eribulin free base.[29] This distinction is vital for accurate dosing and for the correct interpretation of pharmacokinetic and pharmacodynamic data.

Eribulin is commercially supplied as a sterile, clear, and colorless solution for injection, typically at a concentration of 0.5 mg/mL.[7] For long-term storage, the solid powder form is kept at -20°C, protected from light and under nitrogen to ensure stability.[5]

A consolidated summary of the chemical and identification properties for both the free base and the mesylate salt is provided in Table 1.

Table 1: Chemical and Identification Properties of Eribulin and Eribulin Mesylate

Property	Eribulin (Free Base)	Eribulin Mesylate	Source(s)
DrugBank ID	DB08871	DBSALT002427	4
CAS Number	253128-41-5	441045-17-6	4
Chemical Formula	C40​H59​NO11​	C41​H63​NO14​S (or C40​H59​NO11​⋅CH4​O3​S)	4
Molecular Weight (Average)	729.9 g/mol	826.0 g/mol	2
Monoisotopic Mass	729.4088 Da	825.3969 Da	4
IUPAC Name	2-(3-Amino-2-hydroxypropyl)hexacosahydro-3-methoxy-26-methyl-20,27-bis(methylene)11,15-18,21-24,28-triepoxy-7,9-ethano-12,15-methano-9H,15H-furo(3,2-i)furo(2',3'-5,6)pyrano(4,3-b)(1,4)dioxacyclopentacosin-5-(4H)-one	(1S,3S,6S,9S,12S,14R,16R,18S,20R,21R,22S,26R,29S,31R,32S,33R,35R,36S)-20--21-methoxy-14-methyl-8,15-dimethylidene-2,19,30,34,37,39,40,41-octaoxanonacyclo[24.9.2.13,32.13,33.16,9.112,16.018,22.029,36.031,35]hentetracontan-24-one;methanesulfonic acid	2
Common Synonyms/Codes	Eribulin Free Base, E7389, ER-086526, B1939	Halaven, Mevlyq, Eribulin Mesilate, NSC-707389	2
Physical Appearance	Solid powder	Sterile, clear, colorless solution for injection	5
Water Solubility	Not specified (poor)	0.0798 mg/mL	33
Key Database Links	PubChem CID: 11354606; ChEBI: 63587	PubChem CID: 17755248; ChEBI: 70710	2

3.0 Pharmacological Profile

3.1 Mechanism of Action: A Unique Tubulin-Based Antimitotic

Eribulin exerts its potent antineoplastic effects through a unique tubulin-based antimitotic mechanism that distinguishes it from other major classes of microtubule-targeting agents, such as taxanes and vinca alkaloids.[4] Its primary molecular target is tubulin, the protein subunit that polymerizes to form microtubules, which are essential components of the cellular cytoskeleton and the mitotic spindle required for cell division.[4]

The mechanism is characterized by the following key features:

1. Unique Binding Site: Eribulin binds to a small number of high-affinity sites on β-tubulin.[4] Crucially, these binding sites are located at the positive (+)-ends of existing microtubules.[2] This mode of interaction is often described as "end-poisoning" or "end-capping." In contrast, vinca alkaloids bind to a different domain on tubulin, while taxanes bind to the interior of the microtubule polymer.
2. Inhibition of Microtubule Growth: By binding to the growing plus-ends, eribulin acts as a potent inhibitor of microtubule polymerization (the growth phase).[1] It effectively blocks the addition of new tubulin dimers, thereby halting microtubule elongation. A single molecule of eribulin bound to a microtubule end can potently inhibit its growth.[5]
3. No Effect on Shortening: A defining characteristic of eribulin's mechanism is that it does not affect the shortening phase (depolymerization) of microtubules.[4] This is a stark contrast to taxanes (e.g., paclitaxel), which function by hyper-stabilizing microtubules and preventing their disassembly. Eribulin's action is therefore one of pure growth suppression.
4. Tubulin Sequestration: In addition to inhibiting growth, eribulin sequesters free tubulin into non-productive aggregates, further depleting the pool of functional tubulin available for microtubule assembly.[4]

These molecular actions have profound downstream consequences for the dividing cancer cell. The disruption of normal microtubule dynamics prevents the formation of a functional mitotic spindle, the apparatus responsible for segregating chromosomes during mitosis.[4] This leads to a prolonged and, importantly,

irreversible mitotic blockade, arresting the cell cycle at the G2/M transition phase.[4] Unable to complete cell division, the cancer cell ultimately undergoes programmed cell death, or apoptosis.[1] The potency of this mechanism is reflected in its activity against a wide range of cancer cell lines, with half-maximal inhibitory concentrations (

IC50​) typically in the low nanomolar range (0.1 to 10 nM).[32]

3.2 Non-Mitotic and Microenvironmental Effects

Beyond its direct cytotoxic effects on dividing cancer cells, compelling preclinical evidence reveals that eribulin exerts complex, non-mitotic effects on the tumor microenvironment. These actions are thought to contribute significantly to its clinical efficacy, particularly the observed improvements in overall survival that are not always accompanied by proportional gains in progression-free survival.[2] This suggests that eribulin's benefits extend beyond simply halting tumor growth or shrinking tumors.

Key non-mitotic mechanisms include:

• Vascular Remodeling: In human breast cancer models, eribulin treatment has been shown to remodel the chaotic and leaky tumor vasculature. This leads to increased tumor perfusion and better oxygenation, which mitigates tumor hypoxia.[2] Since hypoxia is a major driver of tumor aggressiveness, metastasis, and resistance to therapy, this vascular normalization may render the tumor microenvironment less hostile and more susceptible to subsequent treatments.
• Reversal of Epithelial-Mesenchymal Transition (EMT): EMT is a biological process where epithelial cells lose their cell-cell adhesion and gain migratory and invasive properties, becoming mesenchymal stem cells. This process is critical for metastasis. Eribulin has been shown to induce phenotypic changes consistent with a reversal of EMT.[2] By reverting cancer cells to a less migratory, more epithelial state, eribulin may directly reduce their capacity to invade surrounding tissues and form distant metastases.
• Induction of Cellular Differentiation: In models of soft tissue sarcoma, eribulin treatment has been observed to induce the expression of differentiation antigens. For example, in leiomyosarcoma cells, it increases the expression of smooth muscle antigens, and in liposarcoma cells, it upregulates adipocyte (fat cell) differentiation antigens.[2] This suggests that eribulin may force malignant cells towards a more mature and less aggressive phenotype, a process known as differentiation therapy. This specific effect in liposarcoma models provides a strong biological rationale for the drug's pronounced clinical efficacy in that particular histology.

The existence of these non-mitotic mechanisms helps to explain the apparent paradox sometimes seen in clinical trials, such as the pivotal study in liposarcoma where eribulin produced a substantial overall survival benefit with a more modest effect on progression-free survival.[10] While the direct antimitotic action targets tumor growth (measured by PFS), the microenvironmental effects may make the tumor less aggressive and metastatic over the long term, leading to improved patient survival (measured by OS). This highlights a limitation of traditional trial endpoints like RECIST, which focus on tumor size, and underscores the importance of OS as the ultimate measure of clinical benefit for drugs with such complex mechanisms.

3.3 Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME)

The pharmacokinetic profile of eribulin is well-characterized and possesses several features that are advantageous for clinical use. As the drug is administered exclusively via the intravenous route, considerations of oral absorption are not applicable.[1]

Following intravenous administration, eribulin exhibits linear, dose-proportional pharmacokinetics over a dose range of 0.25 mg/m² to 4.0 mg/m².[4] This predictability means that doubling the dose results in a doubling of drug exposure, simplifying dosing calculations. There is no evidence of significant drug accumulation with the standard weekly administration schedule.[13] The drug's disposition is characterized by a rapid initial distribution phase followed by a prolonged terminal elimination phase.[12]

Eribulin's pharmacokinetic profile is a key clinical differentiator. Many conventional chemotherapeutic agents are heavily metabolized by the hepatic cytochrome P450 enzyme system, creating a high potential for complex and clinically significant drug-drug interactions. The patient population receiving eribulin is often heavily pre-treated and taking multiple supportive care medications, making them particularly vulnerable to such interactions. Eribulin's minimal reliance on CYP450 enzymes for its clearance significantly mitigates this risk. Studies have confirmed that potent inducers of CYP3A4, such as rifampicin, have no clinically relevant effect on eribulin exposure, and eribulin itself does not inhibit or induce major CYP enzymes.[12] This "clean" pharmacokinetic interaction profile provides clinicians with greater confidence when co-administering other medications, reducing the need for complex dose adjustments and minimizing the risk of unexpected toxicity or loss of efficacy.

A summary of key pharmacokinetic parameters is provided in Table 2.

Table 2: Summary of Key Pharmacokinetic Parameters of Eribulin Mesylate

Parameter	Value	Clinical Significance/Commentary	Source(s)
Administration Route	Intravenous	Bypasses gastrointestinal absorption; ensures 100% bioavailability.	1
Pharmacokinetic Linearity	Linear and dose-proportional	Drug exposure increases predictably with dose. No accumulation with weekly dosing.	4
Volume of Distribution (Vd​)	43 L/m² to 114 L/m²	Large volume of distribution indicates extensive distribution into peripheral tissues beyond the plasma compartment.	4
Plasma Protein Binding	49% to 65%	Moderate binding to plasma proteins, primarily albumin.	1
Metabolism Pathway	Negligible	Not significantly metabolized; CYP3A4 plays a minimal role. No major human metabolites are formed.	4
Primary Route of Elimination	Fecal/Biliary Excretion	Approximately 82% of the dose is excreted unchanged in the feces. This is the main clearance pathway.	4
Terminal Half-Life (t1/2​)	Approximately 40 hours	Long half-life supports the intermittent (Days 1 and 8) dosing schedule.	4
Systemic Clearance	1.16 L/hr/m² to 2.42 L/hr/m²	Clearance is reduced in patients with hepatic or renal impairment, requiring dose adjustments.	4

4.0 Clinical Efficacy and Therapeutic Applications

4.1 Approved Indication: Metastatic Breast Cancer (mBC)

Eribulin has established a crucial role in the treatment landscape for heavily pre-treated metastatic breast cancer. In the United States, it is indicated for patients who have previously received at least two chemotherapeutic regimens for metastatic disease, with the stipulation that prior therapy should have included both an anthracycline and a taxane in either the adjuvant or metastatic setting.[4] The European indication is slightly broader, requiring progression after at least one prior chemotherapeutic regimen for advanced disease.[1]

4.1.1 Pivotal Trial in Late-Line Therapy (EMBRACE - Study 305)

The foundational evidence for eribulin's approval in mBC comes from the landmark EMBRACE trial (Eisai Metastatic Breast Cancer Study Assessing Physician's Choice Versus Eribulin).[3] This was a global, randomized, open-label Phase III study that enrolled 762 women with locally advanced or metastatic breast cancer who were heavily pre-treated, having received between two and five prior chemotherapy regimens.[11] Patients were randomized in a 2:1 ratio to receive either eribulin or a single-agent Treatment of Physician's Choice (TPC), which typically consisted of another approved chemotherapy.[9]

The primary endpoint of the study was overall survival (OS). The EMBRACE trial successfully met this endpoint, demonstrating a statistically significant and clinically meaningful improvement in survival for patients treated with eribulin. The median OS was 13.1 months in the eribulin arm compared to 10.6 months in the TPC arm, representing a 2.5-month survival advantage.[9] This finding was practice-changing, as eribulin became the first and only single-agent chemotherapy to demonstrate a significant OS benefit in this late-stage, treatment-refractory patient population.[11]

4.1.2 Trial in Earlier-Line Therapy (Study 301)

To evaluate its efficacy in an earlier setting, a subsequent Phase III trial (Study 301) was conducted. This study compared eribulin directly against capecitabine, a standard-of-care agent, in 1,102 patients with metastatic breast cancer who had received up to two prior chemotherapy regimens for advanced disease.[9] In this head-to-head comparison, eribulin did not demonstrate superiority over capecitabine. There was no statistically significant difference between the two arms for either of the co-primary endpoints:

• Overall Survival (OS): Median OS was 15.9 months for eribulin versus 14.5 months for capecitabine.
• Progression-Free Survival (PFS): Median PFS was 4.1 months for eribulin versus 4.2 months for capecitabine.[9]

The differing outcomes of the EMBRACE and Study 301 trials provide valuable context for eribulin's positioning. While it offers a clear survival advantage in a heavily refractory, third-line-or-later setting where therapeutic options are limited, it performs comparably to, but not better than, a standard agent like capecitabine in an earlier, second-line setting. This suggests that its unique mechanisms of action may confer the greatest relative benefit in tumors that have already developed resistance to multiple standard therapies. This underscores the critical importance of considering the line of therapy and a patient's treatment history when selecting the optimal therapeutic sequence.

4.2 Approved Indication: Unresectable or Metastatic Liposarcoma

Eribulin's second major indication is for the treatment of adult patients with unresectable or metastatic liposarcoma who have previously received an anthracycline-containing regimen.[1] This approval was based on the results of a pivotal Phase III trial that highlighted the drug's remarkable histology-specific activity.

4.2.1 Pivotal Trial in Soft Tissue Sarcoma (Study 309)

Study 309 was a randomized, open-label, multicenter trial that compared eribulin to dacarbazine, an active chemotherapy control.[10] The study enrolled 446 patients with one of two types of advanced soft tissue sarcoma: liposarcoma or leiomyosarcoma, who had received at least two prior lines of systemic therapy.[10]

The primary endpoint of the study was overall survival (OS) in the combined population. The trial met this endpoint, showing a statistically significant improvement in survival for patients treated with eribulin, with a median OS of 13.5 months compared to 11.3 months for those receiving dacarbazine (Hazard Ratio 0.75; p=0.011).[10]

4.2.2 Subgroup Analysis: The Key to Approval

While the overall result was positive, a pre-planned exploratory subgroup analysis revealed a striking difference in efficacy based on tumor histology. The entire survival benefit was driven by the cohort of patients with liposarcoma.

• In the liposarcoma subgroup (n=143): Eribulin demonstrated a dramatic and clinically profound improvement in outcomes compared to dacarbazine.
• Median Overall Survival (OS): 15.6 months for eribulin versus 8.4 months for dacarbazine (HR 0.51).[10]
• Median Progression-Free Survival (PFS): 2.9 months for eribulin versus 1.7 months for dacarbazine (HR 0.52).[10]
• In the leiomyosarcoma subgroup: In stark contrast, there was no evidence of efficacy for eribulin. The median OS was 12.8 months for eribulin versus 12.3 months for dacarbazine, and the median PFS was 2.2 months versus 2.6 months, respectively.[10]

This result is a powerful example of histology acting as a predictive biomarker. The data clearly showed that liposarcoma is highly sensitive to eribulin's effects, while leiomyosarcoma is not. This prevented the drug's significant benefit in liposarcoma from being diluted by the lack of effect in the other subgroup and led the FDA to grant a targeted, histology-specific approval.[10] This finding aligns with the modern oncology paradigm of precision medicine, where treatment is tailored based on specific tumor characteristics. The preclinical observation that eribulin induces adipocyte differentiation in liposarcoma cells provides a potential biological explanation for this specific clinical activity.[2]

4.3 Investigational and Future Directions

The established efficacy of eribulin in breast cancer and liposarcoma has spurred extensive research into its potential in other malignancies and in novel therapeutic combinations.

• Broad Solid Tumor Investigation: Eribulin has been studied in Phase I and II trials across a wide spectrum of advanced solid tumors, including non-small cell lung cancer, prostate cancer, urothelial cancer, melanoma, and various other sarcomas.[2] It has also been investigated in brain cancer, with preclinical studies showing that it can penetrate brain tumor tissue and prolong survival in glioblastoma xenograft models.[2]
• Combination Therapies: A major focus of current research is combining eribulin with other classes of anticancer agents to achieve synergistic effects. The combination with immunotherapy is particularly promising. A joint venture between Eisai and Merck is exploring the combination of eribulin with the PD-1 inhibitor pembrolizumab for the treatment of triple-negative breast cancer and other advanced cancers.[2] The rationale is that eribulin's effects on the tumor microenvironment, such as reversing EMT and modulating immune cell populations, may enhance the efficacy of checkpoint inhibitors. One active Phase 1/2 trial is investigating a multi-drug combination of eribulin, paclitaxel, pembrolizumab, and the antibody-drug conjugate trastuzumab deruxtecan in metastatic solid tumors.[38]
• Novel Formulations: Efforts are underway to improve eribulin's therapeutic index through advanced drug delivery technologies.
• Liposomal Eribulin (E7389 liposomal): A liposomal formulation is currently in Phase I clinical trials. Encapsulating the drug in liposomes can alter its pharmacokinetic properties. Preclinical data suggest this formulation leads to a lower peak plasma concentration (Cmax​) and a longer half-life, which could potentially reduce toxicity while maintaining or enhancing efficacy.[2]
• Antibody-Drug Conjugates (ADCs): Eribulin's high potency makes it an ideal "payload" for ADCs. ADCs use a monoclonal antibody to target a specific antigen on cancer cells, delivering a highly potent cytotoxic agent directly to the tumor while sparing healthy tissues. Eribulin is being actively explored for this application, and various linker-payload constructs are available for research purposes.[2]

5.0 Clinical Administration and Patient Management

5.1 Dosage, Formulation, and Administration

The safe and effective use of eribulin requires strict adherence to established guidelines for dosing, preparation, and administration.

• Standard Dosage: The recommended dose of eribulin mesylate is 1.4 mg/m², with the dose calculated based on the individual patient's body surface area (BSA), which is determined from their height and weight.[7] It is important to note that this dosage refers to the mesylate salt form of the drug; it is equivalent to 1.23 mg/m² of the eribulin free base moiety.[29]
• Treatment Schedule: Eribulin is administered on a 21-day cycle. Within each cycle, the calculated dose is given as an intravenous infusion on Day 1 and Day 8.[7] The period between cycles allows for the patient's body, particularly the bone marrow, to recover from the drug's cytotoxic effects.
• Formulation and Preparation: Eribulin is supplied as a sterile, clear, colorless solution for injection in a single-dose vial.[7] The typical concentration is 0.5 mg/mL of eribulin mesylate (e.g., 1 mg in a 2 mL vial).[1] The required amount should be aseptically withdrawn from the vial. It can be administered undiluted directly from the syringe or, more commonly, diluted in a 100 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline).[7]
• Administration Procedure:
• The infusion should be administered intravenously over a period of 2 to 5 minutes.[7] Some protocols may allow for an infusion time of up to 10 minutes.[29]
• Administration is typically performed through a peripheral intravenous cannula or a central venous access device such as a PICC line, Hickman line, or an implanted portacath, which are often used for patients requiring long-term chemotherapy.[39]
• Critical Incompatibility: Eribulin is incompatible with dextrose-containing solutions. It must not be diluted in or administered through an intravenous line that contains dextrose.[7]
• It should not be mixed or co-infused in the same intravenous line with any other medicinal products.[7]
• After dilution, the solution is stable for up to 4 hours at room temperature or up to 24 hours under refrigeration (4°C).[7]

5.2 Dose Modifications and Management

Proactive monitoring and timely dose adjustments are essential to manage eribulin-related toxicities and ensure patient safety.

• Pre-Dose Monitoring: Before each dose of eribulin (on both Day 1 and Day 8), a complete blood cell (CBC) count with differential must be obtained to assess for myelosuppression.[7] Patients should also be assessed for new or worsening symptoms of peripheral neuropathy.[7] Depending on the patient's risk factors, baseline and periodic monitoring of heart function with an electrocardiogram (ECG) may also be performed to check for QTc interval changes.[39]
• Dose Delays for Acute Toxicity: The administration of eribulin on Day 1 or Day 8 must be delayed if the patient presents with any of the following:
• Absolute Neutrophil Count (ANC) below 1,000/mm³
• Platelet count below 75,000/mm³
• Any Grade 3 or 4 non-hematological toxicity.[7]

The Day 8 dose can be delayed for a maximum of one week. If toxicities do not resolve to Grade 2 or better by Day 15, the dose is omitted for that cycle.7

• Dose Reductions in Special Populations:
• Hepatic Impairment: Eribulin is primarily cleared via biliary excretion, and its exposure is significantly increased in patients with liver dysfunction. Dose reduction is mandatory.
• Mild Impairment (Child-Pugh A): The recommended dose is reduced to 1.1 mg/m².[7]
• Moderate Impairment (Child-Pugh B): The dose is further reduced to 0.7 mg/m².[7]
• Severe Impairment (Child-Pugh C): Eribulin is not recommended for use.[13]
• Renal Impairment: Drug exposure is also increased in patients with kidney dysfunction.
• Moderate Impairment (Creatinine Clearance [CrCl] 30-50 mL/min): The recommended dose is reduced to 1.1 mg/m².[7]
• Severe Impairment (CrCl < 30 mL/min): Eribulin has not been studied in this population and should be omitted or used with extreme caution.[13]

A summary of recommended dose modifications is provided in Table 3 for quick clinical reference.

Table 3: Recommended Dose Modifications for Adverse Reactions and in Special Populations

Condition/Event	Recommended Action/Dose	Source(s)
Part A: Dose Modification for Toxicity
ANC < 1,000/mm³ or Platelets < 75,000/mm³ on day of dosing	Delay administration until ANC ≥ 1,000/mm³ and Platelets ≥ 75,000/mm³.	7
ANC < 500/mm³ for > 7 days	Reduce subsequent doses to 1.1 mg/m².	12
ANC < 1,000/mm³ with fever or infection (Febrile Neutropenia)	Reduce subsequent doses to 1.1 mg/m².	12
Platelets < 25,000/mm³	Reduce subsequent doses to 1.1 mg/m².	12
Platelets < 50,000/mm³ requiring transfusion	Reduce subsequent doses to 1.1 mg/m².	12
Grade 3 or 4 non-hematological toxicities	Delay dose until resolution to ≤ Grade 2, then reduce subsequent doses to 1.1 mg/m².	7
Omission or delay of Day 8 dose in a previous cycle due to toxicity	Reduce subsequent doses to 1.1 mg/m².	12
Any event requiring dose reduction while receiving 1.1 mg/m²	Further reduce dose to 0.7 mg/m².	12
Part B: Dose Modification for Organ Impairment
Mild Hepatic Impairment (Child-Pugh A)	1.1 mg/m²	7
Moderate Hepatic Impairment (Child-Pugh B)	0.7 mg/m²	7
Severe Hepatic Impairment (Child-Pugh C)	Not recommended.	13
Moderate Renal Impairment (CrCl 30-50 mL/min)	1.1 mg/m²	7
Severe Renal Impairment (CrCl < 30 mL/min)	Not studied; use with caution or omit.	13

6.0 Safety, Tolerability, and Risk Management

6.1 Comprehensive Adverse Reaction Profile

The safety profile of eribulin has been well-defined through extensive clinical trials involving over 1,200 patients.[7] The adverse reactions are generally consistent with those expected from a potent cytotoxic chemotherapy agent that targets microtubule function. The most frequently observed and clinically significant toxicities are myelosuppression and peripheral neuropathy. A detailed summary of adverse reactions observed in the pivotal trials for breast cancer and liposarcoma is presented in Table 4.

• Most Common Adverse Reactions (≥25%): The most common side effects reported in patients receiving eribulin include fatigue or asthenia (up to 62%), nausea (up to 41%), alopecia (hair loss, up to 35%), constipation (up to 32%), peripheral neuropathy (up to 29%), abdominal pain (up to 29%), and pyrexia (fever, up to 28%). Hematological toxicities such as neutropenia and anemia are also exceedingly common.[2]
• Other Common Adverse Reactions (≥10%): Other frequently reported events include decreased appetite, headache, musculoskeletal pain (arthralgia, myalgia, back pain), diarrhea, vomiting, cough, dyspnea (shortness of breath), and weight loss.[7]
• Hepatotoxicity: Elevations in serum aminotransferases (ALT) and alkaline phosphatase are common during treatment, with reported rates of ALT elevation ranging from 8% to 83%.[1] However, severe elevations (above 5 times the upper limit of normal) are less frequent (2% to 5%). While isolated cases of "toxic hepatitis" have been mentioned in clinical trial reports, details are scarce, and clinically apparent acute liver injury directly attributable to eribulin appears to be rare. The drug is assigned a LiverTox Likelihood Score of E*, indicating it is an unproven but suspected rare cause of liver injury.[1]

Table 4: Adverse Reactions with ≥25% Incidence in Pivotal Clinical Trials (Breast Cancer and Liposarcoma)

Adverse Reaction	Breast Cancer (EMBRACE Trial) All Grades (%)	Breast Cancer (EMBRACE Trial) Grade 3-4 (%)	Liposarcoma (Study 309) All Grades (%)	Source(s)
Fatigue/Asthenia	54	8	62	7
Neutropenia	52	45	Not specified (common)	7
Alopecia	45	N/A	35	7
Peripheral Neuropathy	35	8	29	7
Nausea	35	1	41	7
Constipation	25	<1	32	7
Anemia	25	2	Not specified (common)	7
Abdominal Pain	Not specified (≥5% to <10%)	Not specified	29	7
Pyrexia (Fever)	21	1	28	7

Note: Frequencies can vary between studies due to differences in patient populations and trial designs. This table presents the most common reactions as reported in the provided sources.

6.2 Warnings, Precautions, and Contraindications

The safe use of eribulin is predicated on awareness of its significant toxicities and adherence to risk mitigation strategies. It is important to note that the provided information does not indicate that eribulin carries a Black Box Warning in the United States.[4]

• Myelosuppression: Severe neutropenia is the most common dose-limiting toxicity of eribulin.[2] It can lead to serious and potentially fatal infections. Febrile neutropenia has been reported.[11] Therefore, regular monitoring of complete blood counts is mandatory prior to each dose. Patients should be counseled to report any signs of infection, such as fever (temperature >100.5°F), chills, cough, or painful urination, immediately.[14]
• Peripheral Neuropathy: Eribulin frequently causes a sensory and motor peripheral neuropathy, characterized by numbness, tingling, burning sensations, or weakness in the hands and feet.[2] This toxicity is cumulative and can become severe and disabling. It was the most common adverse reaction leading to treatment discontinuation (in 5% of patients) in the pivotal breast cancer trial.[4] Careful monitoring for new or worsening symptoms is essential, and dose delays or reductions are often required.
• QTc Interval Prolongation: Eribulin has been shown to cause dose-dependent prolongation of the QTc interval on the electrocardiogram (ECG).[2] This can increase the risk of serious cardiac arrhythmias, including Torsade de Pointes, which can be fatal. Eribulin should be used with caution in patients with a history of heart failure, bradyarrhythmias, or electrolyte abnormalities (hypokalemia, hypomagnesemia), which should be corrected prior to starting treatment. It is contraindicated in patients with congenital long QT syndrome.[16]
• Embryo-Fetal Toxicity: Eribulin is classified as Pregnancy Category D and is expected to cause fetal harm when administered to a pregnant woman.[7] Animal studies have shown it to be teratogenic, causing fetal malformations.[3] Females of reproductive potential must be advised to use effective contraception during treatment and for at least 2 weeks following the final dose. Male patients with female partners of reproductive potential should also use effective contraception during treatment and for 3.5 months after the final dose.[8]
• Lactation: It is unknown whether eribulin is excreted in human milk. Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is contraindicated during treatment and for 2 weeks after the final dose.[1]
• Contraindications: The U.S. prescribing information lists "None" in the main contraindications section.[7] However, based on specific warnings, it is effectively contraindicated in patients with congenital long QT syndrome and in women who are breastfeeding.[9]

6.3 Drug-Drug and Disease-State Interactions

Eribulin presents a notable dichotomy in its interaction profile. While its pharmacokinetic interaction potential is low, its pharmacodynamic interaction potential is significant, requiring careful clinical management.

• Pharmacodynamic Interactions (Major Concern): The primary interaction risk stems from eribulin's ability to prolong the QTc interval. Co-administration with other drugs that share this property can have an additive effect, substantially increasing the risk of life-threatening arrhythmias. There are over 100 drugs with a "major" interaction warning for this reason.[41] This includes, but is not limited to:
• Antiarrhythmics: Amiodarone, dronedarone, sotalol.
• Antipsychotics: Thioridazine, pimozide, chlorpromazine.
• Antibiotics: Clarithromycin, ciprofloxacin.
• Antifungals: Ketoconazole.
• Other Agents: Ondansetron, methadone, cisapride.[4]

Concurrent use of these agents should be avoided. If unavoidable, it requires intensified monitoring with frequent ECGs and electrolyte checks.43

• Pharmacokinetic Interactions (Minor Concern): As detailed previously, eribulin is not a significant substrate, inhibitor, or inducer of the major CYP450 enzymes.[12] Therefore, clinically significant pharmacokinetic interactions with drugs metabolized by these pathways are not expected. This low PK interaction potential is a significant clinical advantage, simplifying the management of concomitant medications.[35]
• Disease-State Interactions: Eribulin should be used with caution in patients with pre-existing conditions that overlap with its toxicity profile. These include:
• Pre-existing cytopenias or risk of infection.
• Hepatic or renal impairment (requires dose adjustment).
• Pre-existing peripheral neuropathy.
• Cardiac conditions, especially heart failure or rhythm disorders.[16]

This dual nature of interaction risk—low for PK, high for PD—demands a sophisticated approach from clinicians. A simple check for CYP450 interactions is insufficient. A thorough medication review focusing on QTc-prolonging potential is paramount for ensuring patient safety.

7.0 Conclusion and Expert Synthesis

Eribulin (Halaven®) stands out in the modern oncologic armamentarium as a testament to the power of natural product-inspired drug discovery and development. Its journey from a rare marine sponge to a globally approved cancer therapy is a remarkable story of chemical innovation overcoming natural scarcity. Eribulin is not merely another cytotoxic agent; it is a mechanistically distinct drug that has carved out a vital niche in the treatment of advanced, difficult-to-treat malignancies.

Its unique "end-poisoning" mechanism of action on microtubule growth, coupled with its intriguing non-mitotic effects on the tumor microenvironment, provides a strong biological basis for its clinical activity. This dual mechanism likely underpins its proven ability to extend overall survival in heavily pre-treated metastatic breast cancer and in unresectable or metastatic liposarcoma—two settings with significant unmet medical need where it has become a standard of care. The histology-specific efficacy observed in sarcoma trials further reinforces the shift towards more precise, biomarker-driven cancer therapy.

The clinical management of eribulin requires a nuanced understanding of its profile. Its favorable pharmacokinetic properties, particularly its minimal reliance on CYP450 metabolism, simplify co-administration with many supportive care medications. However, this must be balanced against a vigilant approach to its significant toxicities. Proactive monitoring and management of myelosuppression (especially neutropenia) and cumulative peripheral neuropathy are cornerstones of its safe use. Furthermore, the risk of QTc prolongation necessitates careful patient selection, baseline cardiac assessment, and a meticulous review of concomitant medications to avoid dangerous pharmacodynamic interactions.

The future of eribulin appears promising. Ongoing investigations into its efficacy in other solid tumors, its role in combination therapies with novel agents like immunotherapy, and the development of next-generation formulations such as liposomes and antibody-drug conjugates hold the potential to further expand its utility and improve its therapeutic index.

In conclusion, eribulin represents a significant therapeutic advance, offering a mechanistically unique option that has demonstrably improved survival outcomes for patients with advanced cancer. Its story serves as a powerful example of how harnessing the chemical complexity of the natural world can lead to the creation of life-extending medicines.

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