Eribulin: Difference between revisions

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[[file:Eribulin CS.png|none|400px]]
[[file:Eribulin CS.png|none|400px]]
|howSupplied=Eribulin mesylate injection, 1 mg/2 mL, in a single-use vial.  One vial per carton.  
|howSupplied=Eribulin mesylate injection, 1 mg/2 mL, in a single-use vial.  One vial per carton.
|storage=Store at 25°C (77°F); excursions permitted to 15° – 30° C (59° -86° F).  Do not freeze.  Store the vials in their original cartons.
|storage=Store at 25°C (77°F); excursions permitted to 15° – 30° C (59° -86° F).  Do not freeze.  Store the vials in their original cartons.
|packLabel=[[file:Eribulin Package.png|none|400px]]
[[file:Eribulin Appearance.png|none|400px]]
|alcohol=Alcohol-Eribulin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|alcohol=Alcohol-Eribulin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=*[[Halaven]]
|brandNames=*[[Halaven]]

Revision as of 17:18, 28 January 2015

Eribulin
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]

Disclaimer

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Overview

Eribulin is an antineoplastic agent and mitotic Inhibitor that is FDA approved for the treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting. Common adverse reactions include alopecia, Weight loss, constipation, anorexia, nausea, anemia, neutropenia, ALT/SGPT, arthralgia, myalgia, asthenia, headache, peripheral neuropathy, fatigue, fever.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Recommended Dose

The recommended dose of HALAVEN is 1.4 mg/m2 administered intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle.

Dose Modification

Assess for peripheral neuropathy and obtain complete blood cell counts prior to each dose.

Recommended dose delays
  • Do not administer HALAVEN on Day 1 or Day 8 for any of the following:
    • ANC < 1,000/mm3
    • Platelets < 75,000/mm3
    • Grade 3 or 4 non-hematological toxicities.
  • The Day 8 dose may be delayed for a maximum of 1 week.
    • If toxicities do not resolve or improve to ≤ Grade 2 severity by Day 15, omit the dose.
    • If toxicities resolve or improve to ≤ Grade 2 severity by Day 15, administer HALAVEN at a reduced dose and initiate the next cycle no sooner than 2 weeks later.
Recommended dose reductions

If a dose has been delayed for toxicity and toxicities have recovered to Grade 2 severity or less, resume HALAVEN at a reduced dose as set out in Table 1. Do not re-escalate HALAVEN dose after it has been reduced.

Instructions for Preparation and Administration

  • Aseptically withdraw the required amount of HALAVEN from the single-use vial and administer undiluted or diluted in 100 mL of 0.9% Sodium Chloride Injection, USP.
  • Do not dilute in or administer through an intravenous line containing solutions with dextrose. Do not administer in the same intravenous line concurrent with the other medicinal products.
  • Store undiluted HALAVEN in the syringe for up to 4 hours at room temperature or for up to 24 hours under refrigeration (40°F or/ 4°C). Store diluted solutions of HALAVEN for up to 4 hours at room temperature or up to 24 hours under refrigeration.
  • Discard unused portions of the vial.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Eribulin in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Eribulin in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Eribulin FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Eribulin in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Eribulin in pediatric patients.

Contraindications

None

Warnings

Neutropenia

Severe neutropenia (ANC < 500/mm3) lasting more than one week occurred in 12% (62/503) of patients in Study 1, leading to discontinuation in <1% of patients. Patients with alanine aminotransferase or aspartate aminotransferase > 3 × ULN (upper limit of normal) experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia than patients with normal aminotransferase levels. Patients with bilirubin > 1.5 × ULN also had a higher incidence of Grade 4 neutropenia and febrile neutropenia.

Monitor complete blood counts prior to each dose; increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. Delay administration of HALAVEN and reduce subsequent doses in patients who experience febrile neutropenia or Grade 4 neutropenia lasting longer than 7 days. Clinical studies of HALAVEN did not include patients with baseline neutrophil counts below 1,500/mm3.

Peripheral Neuropathy

Grade 3 peripheral neuropathy occurred in 8% (40/503) of patients, and Grade 4 in 0.4% (2/503) of patients in Study 1. Peripheral neuropathy was the most common toxicity leading to discontinuation of HALAVEN (5% of patients; 24/503). Neuropathy lasting more than one year occurred in 5% (26/503) of patients. Twenty-two percent (109/503) of patients developed a new or worsening neuropathy that had not recovered within a median follow-up duration of 269 days (range 25-662 days). Monitor patients closely for signs of peripheral motor neuropathy and sensory neuropathy. Withhold HALAVEN in patients who experience Grade 3 or 4 peripheral neuropathy until resolution to Grade 2 or less.

Embryo-Fetal Toxicity

There are no adequate and well-controlled studies of HALAVEN in pregnant women. HALAVEN is a microtubule inhibitor; therefore, it is expected to cause fetal harm when administered to a pregnant woman. Embryo-fetal toxicity and teratogenicity occurred in rats that received eribulin mesylate at approximately half of the recommended human dose based on body surface area. If this drug is used during pregnancy, or if a patient becomes pregnant while taking this drug, she should be apprised of the potential hazard to the fetus.

Prolongation

In an uncontrolled open-label ECG study in 26 patients, QT prolongation was observed on Day 8, independent of eribulin concentration, with no QT prolongation observed on Day 1. ECG monitoring is recommended if therapy is initiated in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia antiarrhythmics and Class III antiarrhythmics, and electrolyte abnormalities. Correct hypokalemia or hypomagnesemia prior to initiating HALAVEN and monitor these electrolytes periodically during therapy. Avoid HALAVEN in patients with congenital long QT syndrome.

Adverse Reactions

Clinical Trials Experience

The following adverse reactions are discussed in detail in other sections of the labeling:

The most common adverse reactions (≥25%) reported in patients receiving HALAVEN were neutropenia, anemia, asthenia/fatigue, alopecia, peripheral neuropathy, nausea, and constipation. The most common serious adverse reactions reported in patients receiving HALAVEN were febrile neutropenia (4%) and neutropenia (2%). The most common adverse reaction resulting in discontinuation of HALAVEN was peripheral neuropathy (5%).

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.

In clinical trials, HALAVEN has been administered to 1,222 patients with multiple tumor types, including 240 patients exposed to HALAVEN for 6 months or longer. The majority of the 1,222 patients were women (82%) with a median age of 58 years (range: 26 to 91 years). The racial and ethnic distribution was Caucasian (83%), Black (5%), Asian (2%), and other (5%).

The adverse reactions described in Table 2 were identified in 750 patients treated in Study 1. In Study 1, patients were randomized (2:1) to receive either HALAVEN (1.4 mg/m2 on Days 1 and 8 of a 21-day cycle) or single agent treatment chosen by their physician (control group). A total of 503 patients received HALAVEN, and 247 patients in the control group received therapy consisting of chemotherapy [total 97% (anthracyclines 10%, capecitabine 18%, gemcitabine 19%, taxanes 15%, vinorelbine 25%, other chemotherapies 10%)] or hormonal therapy (3%). The median duration of exposure was 118 days for patients receiving HALAVEN and 63 days for patients receiving control therapy. Table 2 reports the most common adverse reactions occurring in at least 10% of patients in either group.

Cytopenias

Grade 3 neutropenia occurred in 28% (143/503) of patients who received HALAVEN in Study 1, and 29% (144/503) of patients experienced Grade 4 neutropenia. Febrile neutropenia occurred in 5% (23/503) of patients; two patients (0.4%) died from complications of febrile neutropenia. Dose reduction due to neutropenia was required in 12% (62/503) of patients and discontinuation was required in <1% of patients. The mean time to nadir was 13 days and the mean time to recovery from severe neutropenia (<500/mm3) was 8 days. Grade 3 or greater thrombocytopenia occurred in 1% (7/503) of patients. G-CSF (granulocyte colony-stimulating factor) or GM-CSF (granulocyte–macrophage colony-stimulating factor) was used in 19% of patients who received HALAVEN.

Peripheral Neuropathy

In Study 1, 17 % of enrolled patients had Grade 1 peripheral neuropathy and 3% of patients had Grade 2 peripheral neuropathy at baseline. Dose reduction due to peripheral neuropathy was required by 3% (14/503) of patients who received HALAVEN. Four percent (20/503) of patients experienced peripheral motor neuropathy of any grade and 2% (8/503) of patients developed Grade 3 peripheral motor neuropathy.

Liver Function Test Abnormalities

Among patients with Grade 0 or 1 ALT levels at baseline, 18% of HALAVEN-treated patients experienced Grade 2 or greater ALT elevation. One HALAVEN-treated patient without documented liver metastases had concomitant Grade 2 elevations in bilirubin and ALT; these abnormalities resolved and did not recur with re-exposure to HALAVEN.

Less Common Adverse Reactions

The following additional adverse reactions were reported in ≥5% to <10% of the HALAVEN-treated group:

Postmarketing Experience

The following adverse drug reactions have been identified during post-approval of HALAVEN. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Drug Interactions

Effects of Other Drugs on HALAVEN

No drug-drug interactions are expected with CYP3A4 inhibitors, CYP3A4 inducers or P-glycoprotein (P-gp) inhibitors. Clinically meaningful differences in exposure (AUC) were not observed in patients with advanced solid tumors when HALAVEN was administered with or without ketoconazole (a strong inhibitor of CYP3A4 and a P-gp inhibitor) and when HALAVEN was administered with or without rifampin (a CYP3A4 inducer).

Effects of HALAVEN on Other Drugs

Eribulin does not inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4 enzymes or induce CYP1A2, CYP2C9, CYP2C19 or CYP3A4 enzymes at relevant clinical concentrations. Eribulin is not expected to alter the plasma concentrations of drugs that are substrates of these enzymes.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): There is no FDA guidance on usage of Eribulin in women who are pregnant.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Eribulin in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Eribulin during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Eribulin in women who are nursing.

Pediatric Use

There is no FDA guidance on the use of Eribulin in pediatric settings.

Geriatic Use

There is no FDA guidance on the use of Eribulin in geriatric settings.

Gender

There is no FDA guidance on the use of Eribulin with respect to specific gender populations.

Race

There is no FDA guidance on the use of Eribulin with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Eribulin in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Eribulin in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Eribulin in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Eribulin in patients who are immunocompromised.

Administration and Monitoring

Administration

There is limited information regarding Eribulin Administration in the drug label.

Monitoring

There is limited information regarding Eribulin Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Eribulin and IV administrations.

Overdosage

Overdosage of HALAVEN has been reported at approximately 4 times the recommended dose, which resulted in Grade 3 neutropenia lasting seven days and a Grade 3 hypersensitivity reaction lasting one day. There is no known antidote for HALAVEN overdose.

Pharmacology

Template:Px
Eribulin
Systematic (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
Identifiers
CAS number 253128-41-5
ATC code L01XX41
PubChem 17755248
Chemical data
Formula Template:OrganicBox atomTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox 
Mol. mass 729.90 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability ?
Metabolism ?
Half life ?
Excretion ?
Therapeutic considerations
Licence data

US

Pregnancy cat.

D(US)

Legal status

[[Prescription drug|Template:Unicode-only]](US)

Routes Intravenous

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.

Structure

It has a molecular weight of 826.0 (729.9 for free base). The empirical formula is C40H59NO11•CH4O3S. Eribulin mesylate has the following structural formula:

Pharmacodynamics

There is limited information regarding Eribulin Pharmacodynamics in the drug label.

Pharmacokinetics

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.

Metabolism

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.

Elimination

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.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been conducted with eribulin mesylate.

Eribulin mesylate was not mutagenic in in vitro bacterial reverse mutation assays (Ames test). Eribulin mesylate was positive in mouse lymphoma mutagenesis assays, and was clastogenic in an in vivo rat bone marrow micronucleus assay.

The effects of HALAVEN on human fertility are unknown. Fertility studies have not been conducted with eribulin mesylate in humans or animals. However, nonclinical findings in repeated-dose dog and rat toxicology studies suggest that male fertility may be compromised by treatment with eribulin mesylate. Rats exhibited testicular toxicity (hypocellularity of seminiferous epithelium with hypospermia/aspermia) following dosing with eribulin mesylate at or above 0.43 times the recommended human dose (mg/m2) given once weekly for 3 weeks, or at or above 0.21 times the recommended human dose (mg/m2) given once weekly for 3 out of 5 weeks, repeated for 6 cycles. Testicular toxicity was also observed in dogs given 0.64 times the recommended human dose (mg/m2) weekly for 3 out of 5 weeks, repeated for 6 cycles.

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).

How Supplied

Eribulin mesylate injection, 1 mg/2 mL, in a single-use vial. One vial per carton.

Storage

Store at 25°C (77°F); excursions permitted to 15° – 30° C (59° -86° F). Do not freeze. Store the vials in their original cartons.

Images

Drug Images

{{#ask: Page Name::Eribulin |?Pill Name |?Drug Name |?Pill Ingred |?Pill Imprint |?Pill Dosage |?Pill Color |?Pill Shape |?Pill Size (mm) |?Pill Scoring |?NDC |?Drug Author |format=template |template=DrugPageImages |mainlabel=- |sort=Pill Name }}

Package and Label Display Panel

{{#ask: Label Page::Eribulin |?Label Name |format=template |template=DrugLabelImages |mainlabel=- |sort=Label Page }}

Patient Counseling Information

There is limited information regarding Eribulin Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Eribulin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

Look-Alike Drug Names

There is limited information regarding Eribulin Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.


Eribulin
File:Eribulin.svg
Clinical data
Trade namesHalaven
AHFS/Drugs.comConsumer Drug Information
MedlinePlusa611007
[[Regulation of therapeutic goods |Template:Engvar data]]
Pregnancy
category
  • US: D (Evidence of risk)
Routes of
administration
Intravenous
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
E number{{#property:P628}}
ECHA InfoCard{{#property:P2566}}Lua error in Module:EditAtWikidata at line 36: attempt to index field 'wikibase' (a nil value).
Chemical and physical data
FormulaC40H59NO11
Molar mass729.90 g/mol
3D model (JSmol)
 ☒N☑Y (what is this?)  (verify)

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [3]

Overview

Eribulin is an anticancer drug marketed by Eisai Co. under the trade name Halaven. Eribulin mesylate was approved by the U.S. Food and Drug Administration on November 15, 2010, to treat patients with metastatic breast cancer who have received at least two prior chemotherapy regimens for late-stage disease, including both anthracycline- and taxane-based chemotherapies.[1] It was approved by Health Canada on December 14, 2011 for treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. [2]

Eribulin is also being investigated by Eisai Co. for use in a variety of other solid tumors, including non-small cell lung cancer, prostate cancer and sarcoma.[3]

Eribulin has been previously known as E7389 and ER-086526, and also carries the US NCI designation NSC-707389.

Structure and mechanism

Structurally, eribulin is a fully synthetic macrocyclic ketone analogue of the marine sponge natural product halichondrin B,[4][5] the latter being a potent naturally-occurring mitotic inhibitor with a unique mechanism of action found in the Halichondria genus of sponges.[6][7] Eribulin is a mechanistically-unique inhibitor of microtubule dynamics,[8][9] binding predominantly to a small number of high affinity sites at the plus ends of existing microtubules.[10] Eribulin exerts its anticancer effects by triggering apoptosis of cancer cells following prolonged and irreversible mitotic blockade.[11][12]

A new synthetic route to E7389 was published in 2009.[13]

References

  1. "FDA approves new treatment option for late-stage breast cancer" (Press release). USFDA. 2010-11-15. Retrieved November 15, 2010.
  2. Notice of Decision for HALAVEN
  3. http://www.clinicaltrials.gov/ct2/results?term=eribulin+OR+E7389
  4. Towle MJ, Salvato KA, Budrow J, Wels BF, Kuznetsov G, Aalfs KK, Welsh S, Zheng W, Seletsky BM, Palme MH, Habgood GJ, Singer LA, Dipietro LV, Wang Y, Chen JJ, Quincy DA, Davis A, Yoshimatsu K, Kishi Y, Yu MJ, Littlefield BA (2001). "In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B". Cancer Res. 61 (3): 1013–21. PMID 11221827. Unknown parameter |month= ignored (help)
  5. Yu MJ, Kishi Y, Littlefield BA (2005). "Discovery of E7389, a fully synthetic macrocyclic ketone analogue of halichondrin B". In Newman DJ, Kingston DGI, Cragg, GM. Anticancer agents from natural products. Washington, DC: Taylor & Francis. ISBN 0-8493-1863-7.
  6. Hirata Y, Uemura D (1986). "Halichondrins - antitumor polyether macrolides from a marine sponge". Pure Appl. Chem. 58 (5): 701–710. doi:10.1351/pac198658050701.
  7. Bai RL, Paull KD, Herald CL, Malspeis L, Pettit GR, Hamel E (1991). "Halichondrin B and homohalichondrin B, marine natural products binding in the vinca domain of tubulin. Discovery of tubulin-based mechanism of action by analysis of differential cytotoxicity data". J. Biol. Chem. 266 (24): 15882–9. PMID 1874739. Unknown parameter |month= ignored (help)
  8. Jordan MA, Kamath K, Manna T, Okouneva T, Miller HP, Davis C, Littlefield BA, Wilson L (2005). "The primary antimitotic mechanism of action of the synthetic halichondrin E7389 is suppression of microtubule growth". Mol. Cancer Ther. 4 (7): 1086–95. doi:10.1158/1535-7163.MCT-04-0345. PMID 16020666. Unknown parameter |month= ignored (help)
  9. Okouneva T, Azarenko O, Wilson L, Littlefield BA, Jordan MA (2008). "Inhibition of Centromere Dynamics by Eribulin (E7389) during Mitotic Metaphase". Mol. Cancer Ther. 7 (7): 2003–11. doi:10.1158/1535-7163.MCT-08-0095. PMC 2562299. PMID 18645010. Unknown parameter |month= ignored (help)
  10. Smith JA, Wilson L, Azarenko O, Zhu X, Lewis BM, Littlefield BA, Jordan MA (2010). "Eribulin Binds at Microtubule Ends to a Single Site on Tubulin to Suppress Dynamic Instability". Biochemistry. 49 (6): 1331–7. doi:10.1021/bi901810u. PMC 2846717. PMID 20030375. Unknown parameter |month= ignored (help)
  11. Kuznetsov G, Towle MJ, Cheng H, Kawamura T, TenDyke K, Liu D, Kishi Y, Yu MJ, Littlefield BA (2004). "Induction of morphological and biochemical apoptosis following prolonged mitotic blockage by halichondrin B macrocyclic ketone analog E7389". Cancer Res. 64 (16): 5760–6. doi:10.1158/0008-5472.CAN-04-1169. PMID 15313917. Unknown parameter |month= ignored (help)
  12. Towle MJ, Salvato KA, Wels BF, Aalfs KK, Zheng W, Seletsky BM, Zhu X, Lewis BM, Kishi Y, Yu MJ, Littlefield BA (2011). "Eribulin induces irreversible mitotic blockade: implications of cell-based pharmacodynamics for in vivo efficacy under intermittent dosing conditions". Cancer Res. 71 (2): 496–505. doi:10.1158/0008-5472.CAN-10-1874. PMID 21127197. Unknown parameter |month= ignored (help)
  13. Kim DS, Dong CG, Kim JT, Guo H, Huang J, Tiseni PS, Kishi Y (2009). "New syntheses of E7389 C14-C35 and halichondrin C14-C38 building blocks: double-inversion approach". J. Am. Chem. Soc. 131 (43): 15636–41. doi:10.1021/ja9058475. PMID 19807076. Unknown parameter |month= ignored (help)

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