Annales Pharmaceutiques Françaises (2012) 70, 249—255

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ORIGINAL ARTICLE

Stability of the ready-to-use solutions of eribulin for

intravenous infusion
Stabilité des solutions prêtes à l’emploi d’éribuline pour administration
intraveineuse

S. Poujol a,∗, M. Dell’ova a, K. Bekhtari a,

F. Bressolle a,b, F. Pinguet a

a
Oncopharmacology Laboratory, Val d’Aurelle Cancer Centre, parc Euromédecine, rue des
Apothicaires, 34298 Montpellier, France
b
Clinical Pharmacokinetic Laboratory, Faculty of Pharmacy, Montpellier 1 University,
34093 Montpellier, France

Received 26 March 2012; accepted 8 June 2012

Available online 17 July 2012

KEYWORDS Summary A simple HPLC-UV method was developed to determine the stability of ready-to-
Eribulin; use eribulin solutions under different storage conditions. The developed method was validated
HPLC-UV; with respect to linearity, accuracy, precision and ruggedness. The following admixtures were
Polypropylene prepared: 3-mL polypropylene syringes at concentration of 440 ␮g/mL and multilayer laminate
syringe; polyolefin containers containing 0.9% sodium chloride (50 mL) at concentrations of 15.4 and
Polyolefin bags; 43.3 ␮g/mL. The open-vial stability of eribulin was also evaluated. The following storage con-
Stability; ditions were tested: 4 ◦ C in the refrigerator; 20 ◦ C under room light exposure; and 20 ◦ C with
Different storage light-protection. The drug was also subjected to stress conditions of hydrolysis, oxidation, pho-
conditions; tolysis and thermal degradation. The retention time of eribulin was 4.9 min. Admixtures of
Stress conditions eribulin solutions in vials, syringes or polyolefin bags at clinically relevant concentrations were
physically compatible and chemically stable for at least 14 days at 4 ◦ C in the refrigerator and
at 20 ◦ C with or without any protection against light. Degradation was only found to occur under
oxidation conditions.
© 2012 Elsevier Masson SAS. All rights reserved.

∗ Corresponding author.
E-mail address: sylvain.poujol@montpellier.unicancer.fr (S. Poujol).

0003-4509/$ — see front matter © 2012 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.pharma.2012.06.004
250 S. Poujol et al.

MOTS CLÉS Résumé Une méthode de dosage par CLHP-UV a été développée afin de déterminer la stabilité
Éribuline ; de solutions d’éribuline prêtes à l’emploi conservées dans différentes conditions. La linéarité, la
CLHP-UV ; précision, l’exactitude et la robustesse de la méthode ont été validées. Les situations suivantes
Seringue en ont été étudiées : seringues de 3 mL en polypropylène à la concentration de 440 ␮g/mL, ou
polypropylène ; poches de 50 mL en polyoléfine à des concentrations de 15,4 et 43,3 ␮g/mL. La stabilité des
Poches en flacons entamés a également été évaluée. Les conditions de conservation de ces solutions
polyoléfine ; étaient les suivantes : 4 ◦ C dans un réfrigérateur ; 20 ◦ C exposé à la lumière artificielle et 20 ◦ C
Stabilité ; à l’abri de la lumière. L’éribuline a aussi été soumise à une dégradation forcée par hydrolyse,
Différentes oxydation, photolyse et chauffage. Le temps de rétention de l’éribuline était de 4,9 minutes. Les
conditions de solutions d’éribuline stockées à des concentrations retrouvées cliniquement et contenues dans
stockage ; des flacons préalablement percutés, seringues ou poches, sont physiquement et chimiquement
Dégradations forcées stables au moins 14 jours au réfrigérateur ou à 20 ◦ C exposé ou non à la lumière artificielle. Une
dégradation de l’éribuline n’est observée que dans des conditions de stress avec un oxydant.
© 2012 Elsevier Masson SAS. Tous droits réservés.

Introduction in women with heavily pretreated metastatic breast cancer.

Eribulin mesilate (E7389, Fig. 1) is a non-taxane inhibitor
of microtubule dynamics marketed under the trade name
Halaven® . This drug is derived from halichondrin B, a nat-
ural product isolated from the marine sponge Halichondria
okadai [1—4]. Its mechanism of action differs from other
antitubulin agents, binding predominantly to a small number
of high affinity sites at the plus ends of existing microtubules
[5—7]. Eribulin exerts its anticancer effects by effecting
cell cycle block at G2/M, disruption of mitotic spindle for-
mation, and initiation of apoptosis after prolonged mitotic
blockage [5—9]. In a recent phase 3 study, Embrace [10],
carried out in patients having received between two and
five previous chemotherapy regimens, eribulin has shown a
significant and clinically meaningful improvement in over-
all survival compared with treatment of physician’s choice
Eribulin received approval by the U.S. Food and Drug Admin-
istration in November 2010, and by the European Medicines
Agency in March 2011 for the treatment of advanced breast
cancer patients who have received at least two prior
chemotherapeutic regimens for late-stage disease, includ-
ing both anthracycline- and taxane-based chemotherapies
[11]. Eribulin is also being investigated for use in a variety
of other solid tumors, including non-small cell lung cancer,
prostate cancer and sarcoma [12].
Eribulin mesylate is a clear, colorless, sterile solution
for intravenous administration. Each vial contains 0.88 mg
of eribulin as a 440 ␮g/mL solution in ethanol-water (5:95,
v/v). This drug is administered undiluted or diluted in 0.9%
sodium chloride solution. The recommended dose of eribu-
lin is 1.23 mg/m2 administered intravenously over 2 to 5 min
on days 1 and 8 of a 21-day cycle. This dosage must be
decreased in patients with mild to moderate severe hepatic
impairment and in patients with moderate renal impair-
ment.
To our knowledge, no data are available in the litera-
ture concerning the stability of this compound. Thus, we
undertook to study the effects of temperature and room
light on the stability of eribulin over a period of 14 days.
The aim of our study was to reproduce the different con-
ditions of use and storage encountered at the hospital. In
addition, forced degradation assays were performed under
stress conditions like acid hydrolysis, base hydrolysis, oxida-
tion, heat and UV. The work also includes the validation of
the developed stability-indicating method [13—15].

Figure 1. Chemical structure of eribulin. IUPAC name:
2-(3-Amino-2-hydroxypropyl)hexacosahydro-3-methoxy-
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.
Structure chimique de l’éribuline.
Experimental
Reagents
Eribulin (440 ␮g/mL in the diluent) was purchased from Eisai
26-
Pharmaceuticals (batch 1100578, Teaneck, NJ) and stored at
ambient temperature (20 ± 2 ◦ C) until use. The same batch
number was used throughout the study; drug concentration
was confirmed by a certificate of analysis from the manu-
facturer. Multilayer polyolefin containers (Freeflex® , 50 mL)
Eribulin stability in different containers
were from Fresenius, (Paris, France). Methanol was obtained
from Merck (batch 1607807139, Darmstadt, Germany) and
ammonium acetate from Carlo Erba (batch 8H092249D, Val-
de-Reuil, France). High purity water was prepared by a
Milli-Q water purification system from Millipore (Molsheim,
France). Different vials of eribulin were used to prepare
calibrators and quality control (QC) samples.
Chromatographic apparatus and conditions
A high performance liquid chromatographic (HPLC) method
was used to conduct the analyses. The HPLC system (Shi-
madzu Corporation, Croissy-Beaubourg, France) consisted of
two SIL-10ARvp solvent delivery systems (with dynamic mix-
ing chamber, ref. 228-39001-38), a DGU-14A degasser model,
and a SPD-M10Avp ultraviolet spectrophotometric detector
(ref. 228-400-38). The injections were performed by a Shi-
madzu SIL-10ADvp automatic injector (ref 228-39005-38)
fitted with a 100 ␮L loop and set at 6 ◦ C, and the data were
acquired and processed by Shimadzu CLASS-VP 7 software
(version 6.12). Chromatographic conditions were optimized
to avoid peak deformation or splitting. Best peak shape of
the analyte and relative short analysis time were obtained
on a XBridge C8 column (ref. 186003017, XBridge C8 column,
150 × 4.6 mm, 5 ␮m particle size, Waters, Milford, MA, USA).
The isocratic mobile phase containing mixture of buffer and
methanol in the ratio of 35:75 (v/v) was found to be most
satisfactory as it gave good resolution of drug and degrada-
tion products with reasonably symmetrical sharp peaks. The
buffer consisted of 50 mM ammonium acetate (pH 6.9). The
flow rate of the mobile phase was 1 mL/min. The column
temperature was maintained at 20 ◦ C and the eluent was
monitored at a wavelength of 200 nm. The injection volume
was 100 ␮L.
Preparation of calibration curves and quality
control samples
Aliquot portions of eribulin vials (i.e., in the diluent) were
extemporaneously diluted with 0.9% sodium chloride (1:10,
v/v) and subsequently with mobile phase to prepare calibra-
tion curves (2, 5, 7.5, 10, 15 and 20 ␮g/mL). The peak areas
were plotted against theoretical concentrations. Inter-assay
repeatability of calibration curves was determined for cal-
ibration curves prepared on different days using different
stock solutions (n = 6). Standard calibration curves were
obtained from unweighted least-squares linear regression
analysis of the data. QC samples were prepared in the same
way to provide low, medium and high concentrations: 3.52,
8.8 and 17.6 ␮g/mL. These QC samples were used during the
study to determine accuracy and precision of the method
as well as during stability assays to provide the basis of
accepting or rejecting the run.
Validation
The method was validated according to the European
consensus conference for the practical stability studies of
anticancer drugs, the WHO and ICH guidelines [13—15].
Linear relationships between the peak area and the ana-
lyte concentration were statistically confirmed (lack-of-fit
test). For each point of the calibration standards, the
251
concentrations were back-calculated from the equation of
the linear regression curves. The acceptance criterion for
each back-calculated standard concentration was 5% devia-
tion from the nominal value. The good agreement between
added and back-calculated concentrations was statistically
evaluated. The normal distribution of the residuals (the
difference between nominal and back-calculated concen-
trations) was verified. Moreover, the mean residual values
(or mean predictor error) was computed and compared to
zero (Student t-test); the 95% confidence interval was also
determined.
The between-day precision and accuracy of the method
was validated by analyzing QC samples against a calibration
curve. Determinations were performed with three repli-
cates per QC each day for six separate days. The percent
relative standard deviation (RSD) served as the measure
of precision. The accuracy was evaluated as [mean found
concentration/nominal concentration] × 100. The criteria
for acceptability of data included accuracy within ± 5%
relative error (RE) from the nominal values and a pre-
cision of within ± 5% RSD The lower limit of quantitation
was determined as the concentration of eribulin giving a
signal-to-noise ratio of 10 and both precision and accuracy,
expressed as percentage error, less than or equal to 5%. The
robustness of the developed method was evaluated by assay-
ing eribulin solutions after slight but deliberate changes in
HPLC conditions. The flow rate was changed by 0.1 unit,
from 0.9 to 1.1 mL/min and the effect of column tempera-
ture on resolution was studied at 25 and 30 ◦ C.
Preparation of admixtures
The stability of eribulin solution was evaluated in 3 mL
polypropylene syringes at concentration of 440 ␮g/mL, as
well as in multilayer laminate polyolefin containers contain-
ing 0.9% sodium chloride (50 mL) in order to achieve drug
concentrations of 15.4 and 43.3 ␮g/mL. Sufficient amounts
of stock solutions were therefore added to multilayer lami-
nate polyolefin containers. To ensure that several punctures
can be performed into the same vial, the open-vial stabil-
ity of eribulin was also evaluated in vials pierced with a
18 metal gauge needle and the impact of air exchange was
studied. Needles and syringes were stoppered using tam-
per evident caps (Combi-lock, Codan, Bischwiller, France,
lot K84191-1) to avoid evaporation of ethanolic solution and
individually packed into plastic sachets. Each admixture was
prepared in duplicate (syringes) or in triplicate (vials and
polyolefin containers). All admixtures were prepared under
aseptic conditions in a laminar air flow hood in a GMP class
B clean room reserved for cytostatic drug preparation.
Stability assays were performed under various physi-
cal conditions that could be encountered clinically. Thus,
admixtures were stored at the following conditions:
• 4 ± 2 ◦ C in the refrigerator;
• room temperature (20 ± 2 ◦ C) under room lighting provid-
ing an overall illumination of 1,200 Klux h;
• room temperature under light-protection. The room tem-
perature was controlled by digital display.
The solutions were assayed immediately after prepara-
tion (day 0) and after 1, 3, 7, 10 and 14 days. Immediately
upon sample preparation and at specific time intervals
252 S. Poujol et al.

following storage, 0.15 mL sample was withdrawn from each Table 1 Relative standard deviation (RSD) and recovery
container and analyzed after appropriate dilution in the computed from mean back-calculated concentrations.
mobile phase. Before sampling, each container was man- Coefficient de variation et pourcentage retrouvé à partir des
ually shaken for 1 min to ensure a uniform solution. Samples concentrations moyennes recalculées.
were frozen at −20 ◦ C until analysis. They were found to be
Concentration RSD Recovery
stable for at least 3 weeks under these storage conditions.
(␮g/mL) (%) (%)
Each assay was performed in triplicate.
2 2.98 96.1
Physical stability 5 2.15 103.8
7.5 1.14 103.4
Physical stability was determined by visual inspection and 10 1.72 97.8
pH measurement at two times (T0 and T14 days). Eribulin 15 1.48 96.7
test solutions were visually examined in normal labora- 20 0.94 101.7
tory light whenever samples were withdrawn. Test solutions
with no colour change or any precipitation were defined
as physically stable. Values of pH were measured using a
pH Meter (Hi8417, Hanna Instruments, Kehl am Rhein, Ger- recovery values around the mean back-calculated concen-
many) equipped with an InLab Micro pH glass electrode trations are presented in Table 1. RSD was lower than 3%
(Mettler Toledo, Giessen, Germany). The pH meter was cal- and recovery ranged from 96.1 to 103.8%. The residuals
ibrated with standard buffer solutions (pH 4.01 and 7.01) (differences between nominal and back-calculated concen-
from Hanna Instruments. trations) showed random variations, the number of positive
and negative values being approximately equal. Moreover,
they were normally distributed and centred on zero. Accu-
Forced degradation assay
racy and precision of the method are given in Table 2.
In order to establish whether the analytical method and The lower limit of quantitation was 2 ␮g/mL. The analyt-
the assay were stability-indicating, eribulin at different ical method remained unaffected by slight but deliberate
concentrations was subjected to stress degradation under changes in the analytical conditions (flow rate and column
different conditions. All stress decomposition studies were temperature). The system suitability parameters (tailing
performed at concentrations of 440, 15.4 and 43.3 ␮g/mL. factor, theoretical plates and RSD of area from replicate
Samples were heated (80 ◦ C for 3 h), exposed to UV light injections) are well within the limits [13—15]. Thus, the
(365 nm for 5 h, ultraviolet energy of 200 W h m−2 ) and sub- method was found to be robust with respect to variability in
mitted to degradation under acidic and basic conditions applied conditions.
(phosphate buffer 0.1 M, pH 2.1; acetate buffer 0.02 M, Forced degradation of eribulin solutions was conducted
pH 4.8; ammonium sulfate buffer 0.01 M, pH 9.4). More- to confirm separation of the parent drug from its sec-
over, the drug was exposed to different concentrations ondary product(s) formed during the assay. When eribulin
(4 × 10−6 M to 4 × 10−5 M) of potassium permanganate at was exposed to heat, no decomposition was observed. Like-
20 ◦ C for 1 h. wise, the drug was stable against the effect of photolysis
and in acidic or alkaline conditions (pH 2.1—9.4).
No degradation was observed at a permanganate concen-
tration of 4 × 10−5 M. Mild degradation (about 22%) was
Results observed at a permanganate concentration of 8 × 10−5 M
but the drug gradually underwent greater degradation
HPLC method validation
by increasing permanganate concentration. At 4 × 10−4 M,
The retention time for eribulin was 4.9 min (Fig. 2B). Two eribulin was immediately and totally degraded forming prod-
matrix peaks appeared in the chromatogram at retention ucts at retention times of 3.0 and 3.3 min (Fig. 2). All
times of 5.2 min (peak 2) and 5.4 min (peak 3). To ensure that degradants were well resolved and eluted prior to parent
assay performance and separation were maintained during drug.
the stability study, the number of theoretical plates and
the resolution factors were monitored. Under the chromato-
graphic conditions used, the number of theoretical plates
was approximately 5,500. The resolution factors between Table 2 Between-days precision and accuracy of the
eribulin (peak 1) and the two matrix components were: method.
␣1,2 = 1.4, ␣1,3 = 1.8. The total run time of chromatogram Variabilité inter-jour de la fidélité et exactitude de la méthode.
was about 9 min. A linear calibration plot for this method
Eribulin concentrations Precision Accuracy
was obtained over the calibration range 2—20 ␮g/mL and
(␮g/mL) (RSD, %) (%)
the correlation coefficient obtained was greater than 0.999
(mean r2 , 0.9993, RSD 0.086%), showing an excellent cor- 3.52 2.27 99.2
relation between the peak area and concentration of the 8.8 2.56 101.9
analyte. Inter-assay reproducibility was determined for cal- 17.6 1.91 101.7
ibration curves prepared on different days (n = 6). The
RSD: relative standard deviation.
inter-day slope and Y-intercept of the calibration curve
were 37758 (RSD = 1.54%) and 7877, respectively. RSD and
Eribulin stability in different containers 253

Figure 2. A. LC-UV chromatograms of eribulin solutions (15.4 ␮g/mL) exposed to different concentrations of potassium permanganate
(4 × 10−5 M, black curve; 8 × 10−5 M, red curve and 4 × 10−4 M, green curve). B. LC-UV chromatograms of blank matrix with (black curve)
and without (red curve) eribulin (concentration, 15.4 ␮g/mL). *Not related to the studied compounds.
A. Chromatogrammes (CLHP-UV) de solutions d’éribuline (15,4 ␮g/mL) exposées à différentes concentrations de permanganate de potassium
(4 × 10−5 M, courbe noire ; 8 × 10−5 M, courbe rouge et 4 × 10−4 M, courbe verte). B. Chromatogrammes (CLHP-UV) d’une solution contenant
(courbe noire) ou non (courbe rouge) de l’éribuline (15,4 ␮g/mL). *Pics présents dans le blanc.

Stability study stored at 4 ◦ C in the refrigerator or at room temperature

Results of stability study are given Table 3. The initial
concentration was estimated from samples taken immedi-
ately after preparation and quantified in triplicate against
a calibration curve. Data were expressed in percentage of
the initial drug concentration. The drug concentration never
fell below 97% of the initial concentration over the 14 days
study period. Therefore, eribulin in vials for intravenous
injection, in polypropylene syringes or in multilayer lami-
nate polypropylene containers was stable for 14 days when
with and without any protection against light.
Physical stability and stability testings
In all admixtures, eribulin was physically stable for at least
14 days. For all samples, there was no visible evidence of
precipitation, gas formation, or colour change throughout
the observation period. The pH values measured over the
14-day period remained stable.
254 S. Poujol et al.

Table 3 Stability of eribulin in ready-to-use solutions. Data are expressed in percentage of initial eribulin concentra-
tion ± standard deviation.
Stabilité de solutions prêtes à l’emploi d’éribuline. Les données sont exprimées en pourcentage de la concentration initiale en
éribuline ± écart-type.
Conditions Percent recovery (%)
Day 0 Day 1 Day 3 Day 7 Day 10 Day 14
Vials for intravenous injection pierced with a 18 gauge, 440 g/mL (n = 3)
4 ◦ C, in the refrigerator 100 100.6 ± 0.45 99.1 ± 1.00 100.1 ± 0.25 99.3 ± 0.57 100.1 ± 0.62
20 ± 2 ◦ C under room lighting 100 102.3 ± 2.16 101.8 ± 1.41 102.1 ± 3.04 102.3 ± 2.70 102.5 ± 2.97
20 ± 2 ◦ C under light-protection 100 100.8 ± 1.29 98.8 ± 2.30 100.0 ± 1.36 100.2 ± 0.87 101.3 ± 1.77
Syringe, 440 g/mL (n = 2)
4 ◦ C, in the refrigerator 100 100.4 97.5 96.1 99.6 100.5
20 ± 2 ◦ C under room lighting 100 100.6 101.1 100.7 100.9 101.6
20 ± 2 ◦ C under light-protection 100 98.5 100.0 99.7 100.1 99.1
Polyolefin containers containing 0.9% sodium chloride (50 mL), 15.4 g/mL (n = 3)
4 ◦ C, in the refrigerator 100 100.1 ± 0.88 100.9 ± 0.88 100.7 ± 1.21 99.8 ± 0.83 100.4 ± 0.72
20 ± 2 ◦ C under room lighting 100 100.3 ± 0.64 100.9 ± 1.33 100.4 ± 0.87 100.6 ± 1.81 100.1 ± 2.73
20 ± 2 ◦ C under light-protection 100 99.2 ± 1.14 99.0 ± 1.54 97.2 ± 2.62 98.3 ± 1.49 100.3 ± 3.30
Polyolefin containers containing 0.9% sodium chloride (50 mL), 43.3 g/mL (n = 3)
4 ◦ C, in the refrigerator 100 99.7 ± 0.22 100.1 ± 0.29 100.2 ± 0.93 100.4 ± 0.62 100.8 ± 0.90
20 ± 2 ◦ C under room lighting 100 100.7 ± 1.07 101.3 ± 1.07 101.0 ± 0.59 100.1 ± 1.67 100.8 ± 2.27
20 ± 2 ◦ C under light-protection 100 99.8 ± 0.26 100.2 ± 0.42 99.8 ± 0.47 100.8 ± 0.29 101.2 ± 0.09

Conclusion
The isocratic HPLC-UV method developed proved to be
simple, linear, precise, accurate and specific. The method
was completely validated, showing satisfactory data for all
the parameters tested. Admixtures of eribulin solutions in
open-vials, syringes or polyolefin bags at clinically relevant
concentrations were physically compatible and chemically
stable for at least 14 days at 4 ◦ C in the refrigerator and
20 ◦ C with or without any protection against light. Stress
studies were performed on eribulin and it was found that
no degradation was observed under acidic, basic conditions,
photolytic and upon heat treatment, while the drug was
found to be unstable to oxidative stress. The degraded prod-
ucts were well separated from the pure drug.
Disclosure of interest
The authors declare that they have no conflicts of interest
concerning this article.
Funding: this study was sponsored by Eisai.
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