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1© 2016 Archives of Pharmacy Practice | Published by Wolters Kluwer - Medknow
ABSTRACT
Cancer remains a major cause of hospitalization and death every year. From time to time, new formulations of anticancer drugs are available in the market and draw the concern of healthcare professionals in terms of the superiority, toxicology, and cost‑effectiveness of the new formulations in comparison to the conventional formulation of the same drugs. Doxorubicin, which is a highly potent chemotherapeutic agent, comes with three formulations (pegylated liposomal, nonpegylated liposomal and nonliposomal conventional formulations). English‑language literature in relation to the three formulations has been reviewed to inform the healthcare professionals regarding the differences between these formulations. In terms of efficacy, there is only one study supporting the superiority of liposomal doxorubicin, but there are more data which supports the non‑inferiority of liposomal doxorubicin in comparison to conventional non‑liposomal doxorubicin. It is emphasized that liposomal doxorubicin promotes better toxicology profile than nonliposomal conventional doxorubicin with an increased cost. The cost‑effectiveness of liposomal doxorubicin is not well defined as there are very limited studies in this area. Apart from that, this review highlights the interpatient variability in regards to the clearance and volume of distribution following the administration of liposomal doxorubicin. In conclusion, further studies will be required to better define the superiority of liposomal formulation of doxorubicin regarding the efficacy and dose standardization of liposomal doxorubicin should be sought in the near future.
A comparison between liposomal and nonliposomal formulations of doxorubicin in the treatment of cancer: An updated reviewYik Hoe Ngan, Manish Gupta
School of Pharmacy, Monash University Malaysia, Jalan Lagoon Selatan, 47500 Bandar Sunway, Selangor, Malaysia
Address for correspondence: Dr. Manish Gupta, School of Pharmacy, Monash University Malaysia, Jalan Lagoon Selatan, 47500 Bandar Sunway, Selangor, Malaysia. E‑mail: [email protected]
Key words: Cancer, doxorubicin, liposome
INTRODUCTION
Cancer, which is associated with the rapid and uncontrolled proliferation of cells, is a leading cause of death worldwide. In 2015, it is estimated that there will be 1,658,370 new cases of cancer and account for 589,430 death around the world.[1] There are three distinct approaches to the treatment of cancer, which includes surgical excision, irradiation, and drug therapy.[1,2] In terms of drug therapy, side effects
Review Article
are almost inevitable and are a common cause of therapeutic limitation.[2]
Doxorubicin is a very potent cytotoxic anticancer that directly inhibits topoisomerase II and nucleic acid synthesis.[3] As a result, the proliferation of cancer cells will be terminated. However, anticancer treatment of doxorubicin is always limited by its severe side effects such as cardiotoxicity like as dysrhythmia and heart failure.[3] Fortunately, this
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How to cite this article: Ngan YH, Gupta M. A comparison between liposomal and nonliposomal formulations of doxorubicin in the treatment of cancer: An updated review. Arch Pharma Pract 2016;7:1‑13.
Ngan and Gupta: Liposomal and nonliposomal formulations of doxorubicin
2 Archives of Pharmacy Practice Vol. 7 Issue 1 Jan‑Mar 2016
limitation could be resolved through the clinical application of liposomes.[2-4]
Liposomes are bilayered phospholipid vesicles with an aqueous core that can encapsulate both hydrophilic and hydrophobic drugs.[2] In fact, liposomes can retain the drugs until being disrupted, indicating that they can promote sustained release formulation of drugs.[1-4] Besides, they are also concentrated in malignant tumors, so that enhance the selectivity of the anticancer drugs with reduced toxicity.[2-4]
There are several liposomal formulations of anticancer drugs authorized by United State Food and Drug Administration including doxorubicin.[2] A long-acting form of doxorubicin encapsulated in liposomes has been marketed since the mid-1990s for the treatment of various malignancies.[2-4] It is also known as Doxil in the USA or Caelyx in Europe.[2] This liposomal formulation contains polyethylene glycol (PEG) coated-liposomal doxorubicin, which is capable of targeting doxorubicin to tumor sites. In the present, liposomal doxorubicin is a therapeutic option in the treatment of AIDS-related Kaposi’s sarcoma, metastatic breast cancer, advanced ovarian cancer, and relapsed/refractory multiple myelomas.[5]
To investigate the differences among the formulations of doxorubicin in vivo, a literature search is conducted. It is hypothesized that liposomal doxorubicin encompasses increased efficacy and better toxicology profile compared to nonliposomal conventional doxorubicin.
PHARMACOLOGICAL ACTION OF DOXORUBICIN
Although the exact mode of action remains unknown, the potency of doxorubicin is believed to be associated with topoisomerase II, which is a DNA gyrase and is responsible for the relaxation of supercoiled structure of DNA during transcription.[2,3] Specifically, doxorubicin intercalates in the DNA and stabilizes the DNA–topoisomerase II complex during the transcription process thus prevents the relaxation of the DNA double helix and promotes termination of the process.
Nevertheless, therapeutic limitations of doxorubicin involve severe adverse effects such as dysrhythmia, heart failure, leukocytopenia, moderate to severe nausea, and vomiting and hemorrhage.[2-4] Its cardiotoxicity such as dysrhythmia and heart failure
arises from the formation of cytotoxic free radicals in the heart tissue.[2-4] Therefore, this problem can be resolved by increasing the specificity of doxorubicin through the utilization of liposomes.[2-4]
CLINICAL APPLICATION OF LIPOSOMES IN CHEMOTHERAPY OF CANCER
Liposomes feature an aqueous core, one or more phospholipid membranes with/without coating groups on the surfaces of the membranes.[2,3] These amphiphilic characteristics allow liposomes to carry both hydrophobic and hydrophilic drugs within the lipophilic bilayer or aqueous compartment.[2] For instance, hydrophilic drugs dissolve in the aqueous core or adsorb on the hydrophilic head of the phospholipid bilayer whereas lipophilic drugs are filled with the hydrophobic tails of the bilayer.[2-6]
There are numerous liposome-based anticancer agents being marketed as a liposomal preparation, which are commonly known as Caelyx/Doxil, Myocet, DOX-SL, Lipo-Dox, and DaunoXome. Myocet, Caelyx/Doxil, Liposomal Doxorubicin SUN, and Lipo-Dox are liposomal formulations of doxorubicin whereas DaunoXome is the liposomal formulation of Daunorubicin.[2,3,6]
L IPOSOMAL FORMULATION OF DOXORUBICIN
Specifically, the liposome formulated in Caelyx/Doxil is a type of small unilamellar vesicles (SUV), which is a type of liposomes with a single bilayer and is 30–100 nm in size.[2,3,6] Apart from that, the liposome in the formulation is coated with a hydrophilic polymer, PEG, indicating that it is able to escape from mononuclear phagocytic system uptake and to target the tumor cells through the enhanced permeability and retention effect.[2,6] Doxorubicin in the formulation is manifested in a form of doxorubicin sulfate complex and is covered in the aqueous core of liposome.[2,3]
The main difference between Lipo-Dox and Caelyx/Doxil is the type of liposome being used. The lipid membrane of Caelyx/Doxil is made of hydrogenated soybean phosphatidylcholine and coated with PEG-distearoylphosphatidylethanolamine ( H S P C / P E G - D P S E ) w h e r e a s t h e m e m b r a n e o f L i p o - D o x i s m a d e o f distearoylphosphatidylcholine (DSPC) coated with the same coating material PEG-DSPE.[6] Since DSPC has a higher transition temperature than HSPC,
Ngan and Gupta: Liposomal and nonliposomal formulations of doxorubicin
3Archives of Pharmacy Practice Vol. 7 Issue 1 Jan‑Mar 2016
Lipo-Dox offers higher stability and longer half-life compared to Caelyx/Doxil.[6]
Liposomal Doxorubicin SUN contains a l iposome coated with sodium methoxy PEG-40-carbonyl-DPSE.[4] Although its coating material is different to Caelyx/Doxil, it is proven to be therapeutically equivalent to Caelyx/Doxil.[5]
Myocet is a type of non-pegylated liposomal doxorubicin (non-PLD) composed of SUV. Similar to Caelyx/Doxil, doxorubicin is located within the aqueous core of the liposome but is manifested in a form of doxorubicin citrate complex.[2,5]
LITERATURE REVIEW
Data sources and selectionIn respect of research strategies, a search of PubMed, Cochrane Library, and EMBASE using the MeSH search terms doxorubicin, liposome, and cancer was performed. Additional search terms are the brand name of doxorubicin which includes DOX-SL, Lipo-Dox, Doxil, Caelyx, Lipo-Dox, and DaunoXome. All articles being reviewed were primary sources and published within the last 5 years (2010–September 2015) except one primary source, which is thought to be vitally important for the quality of life analysis. Apart from that, secondary sources such as textbook, systematic reviews, and meta-analysis were used as a background reference to support the analysis of the primary sources [Table 1].
PHARMACOKINETIC
Large area under the curve (AUC), slow clearance rate (CL), small distribution volume (VD), and long elimination half-time (t½) characterize the pharmacokinetics (PK) of pegylated liposomal doxorubicin (PLD).[8,9,22] The VD of PLD is close to the blood volume so that the PK of PLD undergoes single compartment model.[8,9] The pegylated lipids in the liposomes result in a long circulation half-time, typically 3–4 days.[8,9]
Nonliposomal conventional doxorubicin has a large VD indicating that a significant amount of the drug is taken up in normal tissues.[8,22] Apart from that, the AUC for conventional nonliposomal doxorubicin is about three orders of magnitude smaller than PLD resulting in a CL rate about three orders of magnitude larger. The t½ for conventional doxorubicin is about 20–25 h.[8,9]
Non-PLD has a shorter t½ than PLD but a longer t½ than conventional nonliposomal doxorubicin.[7] It is due to the absence of PEG coating in the formulation, which indicates that it can be easily taken up by the reticuloendothelial system (RES) and undergo metabolism.[5]
Despite the fact that there are imperative benefits associated with PLD and non-PLD than nonliposomal conventional doxorubicin, its interpatient variability in terms of PKs are more clinically significant in comparison to conventional nonliposomal doxorubicin.[8,9]
Regarding the nonliposomal conventional doxorubicin, factors contributing to interpatient variability are hepatic impairment, patient age and polymorphism in efflux transporter and metabolizing enzymes.[27] Doxorubicin is hepatically cleared by carbonyl reductases (CBR) and cytochrome P-450 enzymes, especially CBR1, CBR3, CYP3A4, CYP2C9, and CYP2D6, which implies that genetic polymorphism of CBR affects the CL of doxorubicin.[27] In relation to that, patients with hepatic impairment as well as elderly population are less capable to metabolize doxorubicin due to their insufficient metabolizing enzymes of doxorubicin.[27] Apart from that, a various subfamily of ATP-binding cassette (ABC) is responsible for pumping out doxorubicin, including ABCB1, ABCB5, ABCB8, ABCC5, and ABCG2. Provided that, polymorphism of the efflux transporter ABC can positively or negatively affect the plasma concentration of doxorubicin.[27]
In comparison to conventional nonliposomal doxorubicin, PLD and non-PLD undertake a more complicated metabolizing pathway.[9] Theoretically, the CL of liposomes depends upon the RES, involving monocytes, macrophages, and dendritic cells. Hence, besides the metabolism of doxorubicin in the aqueous core, the CL of both PLD and non-PLD bears upon the immune system as well as the RES function of different individuals.[8,9,22] Deterioration of immunity is common in the aging population, which is scientifically known as immunosenescence.[28] Hence, the CL of doxorubicin in an elderly patient is further reduced which is possible to prolong t½ and AUC of doxorubicin. In spite of the unclear reason, gender is discovered to be an important contributing factor for the CL of liposomal doxorubicin. Clinical significantly, female patients have a lower CL of liposomal doxorubicin than male patient.[8] Although the exact reason for this phenomenon remains unknown, it is
Ngan and Gupta: Liposomal and nonliposomal formulations of doxorubicin
4 Archives of Pharmacy Practice Vol. 7 Issue 1 Jan‑Mar 2016
Tabl
e 1:
Syn
opsi
s of
orig
inal
art
icle
s re
late
d to
lipo
som
al fo
rmul
atio
n of
dox
orub
icin
pre
sent
in th
e m
arke
tSt
udy
Setti
ngPa
rtic
ipan
ts a
nd
follo
w‑u
pSt
udy
desi
gnIn
terv
entio
n ev
alua
ted
Mai
n ou
tcom
esFi
ndin
gsLi
mita
tions
Ber
ger e
t al.[6
]M
agee
‑Wom
en
Hos
pita
l, U
nive
rsity
of
Pitt
sbur
gh
Med
ical
C
ente
r. 20
12
18 p
atie
nts
treat
ed
with
lipo
som
al
doxo
rubi
cin
Ret
rosp
ectiv
e st
udy
Lipo
som
al
doxo
rubi
cin
RR
s an
d to
xici
ty
asso
ciat
ed
with
lipo
dox
No
patie
nts
had
a co
mpl
ete
or p
artia
l res
pons
e to
lipo
dox.
D
isea
se c
ontro
l rat
e of
11%
Und
erpo
wer
ed s
ampl
e si
ze a
nd n
o st
atis
tical
dat
a pr
ovid
ed, i
ndic
atin
g th
e la
ck
of s
tatis
tical
sig
nific
ance
. H
igh
cont
amin
atio
n du
e to
pre
treat
men
t prio
r to
lipos
omal
dox
orub
icin
Was
le e
t al.[7
]11
Aus
trian
an
d 1
Italia
n ca
ncer
cen
ter.
Mar
ch 2
008‑
D
ecem
ber
2013
326
patie
nts
with
ly
mph
opro
lifer
ativ
e di
seas
e re
ceiv
ed, a
t le
ast,
one
dose
of
Myo
cet,
whi
ch is
a
nonp
egyl
ated
form
of
lipos
omal
dox
orub
icin
Obs
erva
tiona
l stu
dyM
yoce
tE
valu
atio
n of
toxi
city
gr
aded
acc
ordi
ng
to N
CI C
TCA
E,
vers
ion
4.0
The
mos
t com
mon
gr
ade
3/4
toxi
citie
s w
ere
hem
atol
ogic
toxi
city
, inc
ludi
ng
leuk
open
ia, n
eutro
peni
a,
thro
mbo
cyto
peni
a an
d fe
brile
neu
trope
nia
Con
tam
inat
ions
dur
ing
the
stud
y pe
riod
wer
e no
t tak
en
into
acc
ount
as
som
e pa
tient
s re
ceiv
ed n
ot o
nly
Myo
cet b
ut
also
oth
er c
ytot
oxic
dru
gs
such
as
cycl
opho
spha
mid
e,
vinc
ristin
e, p
redn
ison
e,
and
ritux
imab
. Add
ition
ally,
ba
selin
e ch
arac
teris
tic o
f th
e pa
tient
s su
ch a
s or
gan
func
tion
had
not b
een
take
n in
to c
onsi
dera
tion
of th
e st
udy
La‑B
eck
et a
l.[8]
Unk
now
n se
tting
s70
pat
ient
s >1
8 ye
ars
of a
ge
with
his
tolo
gica
lly
or c
ytol
ogic
ally
co
nfirm
ed s
olid
tum
ors
or K
apos
i’s s
arco
ma
and
adeq
uate
org
an
func
tion
with
out p
rior
cum
ulat
ive
treat
men
t of
dox
orub
icin
Ther
e ar
e 3
stud
ies
bein
g co
nduc
ted.
st
udy
1 an
d 2
are
obse
rvat
iona
l stu
dies
w
here
as s
tudy
3
is a
rand
omiz
ed
cont
rolle
d tri
al
PLD
The
rela
tions
hip
betw
een
age
as
wel
l as
gend
er a
nd
the
CL
of P
LD
The
fact
ors
affe
ctin
g th
e C
L of
PLD
are
diff
eren
t in
com
paris
on to
non
lipos
omal
do
xoru
bici
n. F
emal
e pa
tient
ha
s lo
wer
CL
of P
LD th
an
mal
e (P
<0.0
001)
. Apa
rt fro
m
that
, pat
ient
s <6
0 ye
ars
old
have
hig
her C
L th
an p
atie
nts
>60
year
s ol
d (P
<0.0
001)
The
deta
iled
co‑in
terv
entio
n ha
d no
t bee
n re
porte
d.
Unk
now
n se
tting
s lim
it th
e cl
inic
al a
pplic
abili
ty
of th
e re
sults
Boe
rs‑S
onde
ren
et a
l.[9]
Sin
gle
cent
er
in F
inla
nd.
Unk
now
n tim
elin
e
20 p
atie
nts
with
hi
stol
ogic
al p
rove
n ad
vanc
ed b
reas
t, en
dom
etria
l or o
varia
n ca
ncer
s, w
ho a
re
mor
e th
an 1
8 ye
ars
old
and
have
life
ex
pect
ancy
of m
ore
than
12
wee
ks
Pha
se Ib
clin
ical
tria
lC
aely
x in
co
mbi
natio
n w
ith
tem
siro
limus
To a
sses
s th
e fa
ctor
s af
fect
ing
the
PK
/PD
of
Cae
lyx
The
cael
yx e
xpos
ure
(log
AU
C) w
as h
ighe
r in
patie
nts
who
exp
erie
nced
rash
(P
=0.0
02) a
nd m
ucos
itis
(P=0
.001
) com
pare
d to
pat
ient
s w
ho d
id n
ot
expe
rienc
e th
ese
adve
rse
even
ts. A
dditi
onal
ly, th
ere
is n
o re
latio
nshi
p be
twee
n C
aely
x ex
posu
re a
nd th
e oc
curr
ence
of c
omm
on s
ide
effe
cts
of C
aely
x su
ch a
s le
ukoc
ytop
enia
, sto
mat
itis,
an
d ha
nd‑fo
ot s
yndr
ome
Und
erpo
wer
ed s
ampl
e si
ze
indi
cate
s th
e qu
estio
nabl
e si
gnifi
canc
e in
clin
ical
set
tings
Cont
d...
Ngan and Gupta: Liposomal and nonliposomal formulations of doxorubicin
5Archives of Pharmacy Practice Vol. 7 Issue 1 Jan‑Mar 2016
Tabl
e 1:
Con
td...
Stud
ySe
tting
Part
icip
ants
and
fo
llow
‑up
Stud
y de
sign
Inte
rven
tion
eval
uate
dM
ain
outc
omes
Find
ings
Lim
itatio
ns
Hun
ault‑
Ber
ger
et a
l.[10]
26 c
ente
rs
in F
inla
nd.
Mar
ch 2
002‑
O
ctob
er 2
006.
O
utco
me
data
was
up
date
d on
1
Apr
il 20
09
60 u
ntre
ated
pat
ient
s ag
ed 5
5 ye
ars
or m
ore
with
non
Bur
kitt’
s,
Phi
lade
lphi
a ch
rom
osom
e‑ne
gativ
e or
BC
R‑A
BL
nega
tive
acut
e ly
mph
obla
stic
le
ukem
ia w
ithou
t se
vere
arr
hyth
mia
, co
rona
ry a
rtery
di
seas
e, a
cute
he
art f
ailu
re, l
eft
vent
ricul
ar e
ject
ion
fract
ion
<50%
, ren
al
or li
ver d
ysfu
nctio
n,
posi
tivity
for h
uman
im
mun
odefi
cien
cy
viru
s, o
r psy
chia
tric
dise
ase
RC
TC
ontin
uous
‑ in
fusi
on d
oxor
ubic
in
in c
ombi
natio
n w
ith v
incr
istin
e on
one
arm
or
PLD
(Cae
lyx)
and
st
anda
rd v
incr
istin
e on
the
othe
r arm
Prim
ary
Out
com
e:
com
posi
te e
ffica
cy
and
toxi
city
con
sist
ing
of c
ontin
uous
co
mpl
ete
rem
issi
on
rate
, hem
atol
ogic
and
ex
tra‑h
emat
olog
ic
toxi
city
. Sec
onda
ry
Out
com
e: c
ompl
ete
rem
issi
on ra
te, s
afet
y,
cum
ulat
ive
inci
denc
e of
rela
pse
and
failu
re,
cum
ulat
ive
inci
denc
e of
dea
th in
firs
t co
mpl
ete
rem
issi
on
and
treat
men
t‑rel
ated
de
ath,
eve
nt‑fr
ee
surv
ival
and
OS
Des
pite
the
fact
that
m
ore
patie
nts
in
conv
entio
nal d
oxor
ubic
in
arm
dea
d, c
onve
ntio
nal
doxo
rubi
cin
(90%
) gav
e ris
e to
hig
her c
ompl
ete
rem
issi
on
rate
afte
r tw
o in
duct
ion
cycl
es
in c
ompa
rison
to P
LD (7
2%).
Apa
rt fro
m th
at, p
egyl
ated
lip
osom
al d
oxor
ubic
in
decr
ease
d th
e to
xici
ty o
f do
xoru
bici
n in
term
s of
m
yelo
supp
ress
ion
(P=0
.005
‑0.
9), i
nfec
tions
(P=0
.04‑
0.12
) and
car
diot
oxic
ity
(P=0
.12)
. Des
pite
the
redu
ced
toxi
city
, peg
ylat
ed
doxo
rubi
cin
does
not
pr
omot
e be
tter s
urvi
val r
ate
Som
e re
sults
inte
rpre
ted
by th
e ar
ticle
can
be
due
to c
hanc
e (P
>0.0
5)
Fieg
l et a
l.[11]
Aus
tralia
. 20
03‑2
009
129
cons
ecut
ive
patie
nts
with
ad
vanc
ed b
reas
t ca
ncer
, who
re
ceiv
ed P
LD a
s m
onot
hera
py w
ithin
lic
ense
d ap
prov
al
Obs
erva
tiona
l ph
ase
IV s
tudy
PLD
Res
pons
e to
PLD
w
hich
incl
udes
to
xici
ty a
nd e
ffica
cy
asso
ciat
ed w
ith P
LD
Ther
e w
ere
enco
urag
ing
resu
lts w
ith P
LD a
s a
mon
o‑th
erap
eutic
age
nt I
the
treat
men
t of m
etas
tasi
zed
brea
st c
ance
r. Th
e m
ost
com
mon
sid
e ef
fect
obs
erve
d w
as d
ose‑
depe
nden
t PP
E
The
artic
le is
dee
med
to
be
a cr
oss‑
sect
iona
l st
udy,
indi
catin
g th
at
larg
e pe
rform
ance
bia
s is
alm
ost i
nevi
tabl
e
Won
g et
al.[1
2]A
sing
le
inst
itutio
n in
S
inga
pore
. U
nkno
wn
timel
ine
84 A
sian
s w
ho a
re
new
ly d
iagn
osed
with
lo
cally
adv
ance
d or
m
etas
tatic
bre
ast
canc
er
Clin
ical
tria
lN
onlip
osom
al
doxo
rubi
cin
PK
and
hem
atol
ogic
to
xici
ties
of
doxo
rubi
cin
Incr
ease
d bo
dy fa
t co
mpo
sitio
n, e
spec
ially
in
tra‑a
bdom
inal
fat
cont
ent,
is a
ssoc
iate
d w
ith
incr
ease
d do
xoru
bici
n ex
posu
re a
nd ra
te o
f gra
de
4 le
ukop
enia
(P<0
.000
1).
Ther
efor
e, in
divi
dual
s w
ith
exce
ssiv
e bo
dy fa
t in
rela
tive
to L
BM
will
hav
e a
high
risk
of
dox
orub
icin
‑ass
ocia
ted
toxi
city
, in
rega
rdle
ss o
f BM
I. Fu
rther
mor
e, b
ody
surfa
ce
area
doe
s no
t det
erm
ine
the
PK
and
toxi
city
of d
oxor
ubic
in
Bas
elin
e ch
arac
teris
tics
such
as
pat
ient
age
are
not
take
n in
to c
onsi
dera
tion
Cont
d...
Ngan and Gupta: Liposomal and nonliposomal formulations of doxorubicin
6 Archives of Pharmacy Practice Vol. 7 Issue 1 Jan‑Mar 2016
Tabl
e 1:
Con
td...
Stud
ySe
tting
Part
icip
ants
and
fo
llow
‑up
Stud
y de
sign
Inte
rven
tion
eval
uate
dM
ain
outc
omes
Find
ings
Lim
itatio
ns
Jurc
zak
et a
l.[13]
Dat
a co
llect
ed
in P
olis
h Ly
mph
oma
Res
earc
h G
roup
. Ti
mel
ine
unkn
own
610
new
ly d
iagn
osed
N
HL
Cau
casi
ans
Ret
rosp
ectiv
e an
alys
isN
onlip
osom
al
doxo
rubi
cin,
no
n‑P
LD a
nd P
LD
Res
pons
e to
tre
atm
ent a
ccor
ding
to
Che
son
crite
ria,
card
ioto
xici
ty, a
nd O
S
Res
pons
e to
trea
tmen
t ac
cord
ing
to C
heso
n cr
iteria
in
patie
nts
treat
ed w
ith li
poso
mal
do
xoru
bici
n is
non
infe
rior
com
pare
d to
non
lipos
omal
do
xoru
bici
n. M
oreo
ver,
the
OS
of p
atie
nts
with
hig
h ris
k of
fata
l car
diac
eve
nts
is
com
para
ble
to th
ose
patie
nts
with
low
risk
of c
ardi
ac fa
tal
even
t, in
dica
ting
that
lipo
som
al
doxo
rubi
cin
incr
ease
s th
e O
S in
pat
ient
s w
ith h
igh‑
risk
fata
l car
diac
eve
nts
In re
latio
n to
OS
, the
ob
serv
ed n
onin
ferio
rity
of
lipos
omal
dox
orub
icin
in
com
paris
on to
non
lipos
omal
do
xoru
bici
n ca
n du
e to
cha
nce
(P=0
.9)
Lotri
onte
et
al.[1
4]U
nkno
wn
setti
ngs
52 p
atie
nts
with
no
nmet
asta
tic c
ance
rR
CT
Non
‑PLD
‑bas
ed
regi
men
and
E
PI‑b
ased
trea
tmen
t
TDI e
xam
ined
sy
stol
ic fu
nctio
nLo
wer
car
diot
oxic
ity is
ob
serv
ed in
the
arm
with
no
npeg
ylat
ed li
poso
mal
do
xoru
bici
n‑ba
sed
regi
men
(P=0
.006
)
Unk
now
n se
tting
s lim
it th
e cl
inic
al a
pplic
abili
ty
of th
e da
ta
Cha
stag
ner
et a
l.[15]
Unk
now
n lo
catio
n.
Oct
ober
20
10‑J
anua
ry
2013
13 c
hild
ren
aged
6‑
17 y
ears
old
w
ith h
isto
logi
cally
do
cum
ente
d m
alig
nant
glio
ma
Pha
se I
clin
ical
stu
dyM
yoce
tM
axim
um R
D a
nd P
KD
espi
te th
e ac
cept
able
sa
fety
pro
mot
ed b
y M
yoce
t, P
K d
iffer
ence
s be
twee
n th
e ad
ult a
nd th
e pe
diat
ric
popu
latio
n re
mai
n un
clea
r. La
rge
inte
rpat
ient
var
iabi
lity
in te
rms
of P
K w
as
high
light
ed in
this
stu
dy
Und
erpo
wer
ed s
ampl
e si
ze
indi
cate
s th
e qu
estio
nabl
e si
gnifi
canc
e in
clin
ical
set
tings
Xu
et a
l.[16]
Chi
na. 2
006
22 C
hine
se p
atie
nts
with
his
tolo
gica
lly o
r cy
tolo
gica
lly c
onfir
med
br
east
can
cer
Cro
ss‑o
ver R
CT
with
4‑w
eek
was
h‑ou
t tim
e
2 P
LD p
rodu
ctD
as s
oftw
are
calc
ulat
ed P
K p
rofil
eTh
e P
K d
emon
stra
ted
by
the
2 pr
oduc
ts w
as s
imila
r. In
com
paris
on to
Eur
opea
n st
udy
rega
rdin
g th
e P
K
profi
le, T
he C
L an
d V
D o
f the
C
hine
se p
atie
nts
are
high
er
than
Eur
opea
n pa
tient
s.
Ther
apeu
tic e
ffica
cy w
as
not o
bser
ved
in th
is s
tudy
Und
erpo
wer
ed s
ampl
e si
ze
indi
cate
s th
e qu
estio
nabl
e si
gnifi
canc
e in
clin
ical
set
tings
. Th
e na
me
of th
e PL
D p
rodu
ct
had
not b
een
men
tione
d.
Unk
now
n ra
ndom
izat
ion
proc
edur
e in
dica
tes
the
poss
ibilit
y of
sel
ectio
n bi
as.
Unk
now
n bl
indi
ng in
dica
tes
the
poss
ibilit
y of
per
form
ance
bia
sTu
rini e
t al.[1
7]Ita
lian,
G
erm
an,
and
Fren
ch.
2013
‑201
4
Onc
olog
ists
and
on
colo
gy n
urse
sC
ross
‑sec
tiona
l st
udy
(an
onlin
e su
rvey
)
Che
mot
hera
pyTo
ass
ess
the
chem
othe
rapy
‑ in
duce
d na
usea
and
vo
miti
ng d
irect
cos
t
It hi
ghlig
hted
the
sign
ifica
nt
cost
of c
hem
othe
rapy
‑indu
ced
naus
ea a
nd v
omiti
ng o
n th
e N
HS
in E
urop
ean
Cou
ntrie
s
It is
que
stio
nabl
e th
at th
e fin
ding
may
not
be
appl
icab
le
to A
sian
cou
ntrie
s
Mon
k et
al.[1
8]12
4 ce
nter
s in
21
cou
ntrie
s.
Apr
il 20
05‑
May
200
7
672
patie
nts
with
hi
stol
ogic
ally
co
nfirm
ed p
ithel
ial
ovar
ian,
fallo
pian
tu
be, o
r prim
ary
perit
onea
l car
cino
ma
Pha
se II
I RC
TTr
abec
tedi
n pl
us
PLD
and
PLD
To a
sses
s th
e sa
fety
an
d ef
ficac
y of
the
two
inte
rven
tion
It co
nfirm
ed th
e su
perio
rity
of th
e co
mbi
natio
n tre
atm
ent
com
pare
d to
sin
gle
treat
men
t. (P
<0.0
5)
No
blin
ding
indi
cate
s th
e ris
k of
per
form
ance
bia
s
Cont
d...
Ngan and Gupta: Liposomal and nonliposomal formulations of doxorubicin
7Archives of Pharmacy Practice Vol. 7 Issue 1 Jan‑Mar 2016
Tabl
e 1:
Con
td...
Stud
ySe
tting
Part
icip
ants
and
fo
llow
‑up
Stud
y de
sign
Inte
rven
tion
eval
uate
dM
ain
outc
omes
Find
ings
Lim
itatio
ns
Criv
ella
ri et
al.[1
9]M
ultin
atio
nal.
Rec
ruitm
ent
from
N
ovem
ber
2005
and
D
ecem
ber
2007
. Fo
llow
‑up
42 m
onth
s
77 m
ultin
atio
nal
elde
rly (>
66 y
ears
ol
d) p
atie
nts
with
end
ocrin
e no
nres
pons
ive
(ER
<10
%; a
nd
PgR
<10
%)
brea
st c
ance
r
Pha
se II
I RC
TP
LD re
gim
en
and
met
rono
mic
cy
clop
hosp
ham
ide
plus
met
hotre
xate
The
prim
ary
endp
oint
is B
CFI
. S
econ
dary
out
com
es
incl
uded
tole
rabi
lity,
ad
vers
e ev
ents
, an
d qu
ality
of l
ife
The
occu
rren
ce o
f BC
FI
was
sim
ilar i
n tw
o ar
ms.
No
card
iac
toxi
city
had
bee
n ob
serv
ed. P
atie
nts
on P
LD
repo
rted
wor
se Q
L sc
ores
th
an th
ose
on n
on‑P
LD
for a
ll m
easu
res
exce
pt
for n
ause
a an
d vo
miti
ng.
The
mea
sure
s co
nsis
t of
phys
ical
wel
l‑bei
ng, f
unct
iona
l pe
rform
ance
, ove
rall
dise
ase/
treat
men
t bur
den,
muc
osa
infla
mm
atio
n of
the
mou
th
No
allo
catio
n co
ncea
lmen
t in
dica
tes
the
risk
of s
elec
tion
bias
. No
blin
ding
indi
cate
s th
e ris
k of
per
form
ance
bia
s
Lee
et a
l.[20]
Sou
th K
orea
. 20
13A
Mar
kov
mod
el w
ith
a 10
‑yea
r tim
e ho
rizon
Cos
t‑util
ity a
naly
sis
PLD
/car
bopl
atin
ve
rsus
pac
litax
el/
carb
opla
tin
QA
LYP
LD/c
arbo
plat
in c
ombi
natio
n is
mor
e ef
fect
ive
and
cost
ly
than
pac
litax
el/c
arbo
plat
in
com
bina
tion,
with
an
addi
tiona
l US
D 2
1,65
8 Q
ALY
Ther
e is
a v
aria
tion
in P
LD
cost
and
PLD
adm
inis
tratio
n co
st. A
dditi
onal
ly, p
atie
nts
are
assu
med
to a
ccep
t six
do
ses
of c
hem
othe
rapy
on
aver
age
from
the
diag
nosi
s of
ova
rian
canc
er u
ntil
deat
hS
taro
poli
et a
l.[21]
Clin
ical
D
ata
of It
aly.
20
01‑2
011
108
patie
nts
with
hi
stol
ogic
ally
co
nfirm
ed o
varia
n ca
ncer
Ret
rosp
ectiv
e co
hort
stud
yO
n th
e ex
posu
re
arm
, the
pat
ient
s ar
e tre
ated
with
PLD
. On
the
cont
rol a
rm, t
he
patie
nts
are
treat
ed
with
oth
er d
rugs
su
ch a
s to
pote
can,
ge
mci
tabi
ne,
etop
osid
e. P
atie
nts
unde
rwen
t P
LD h
ad h
igh
plat
inum
‑sen
sitiv
ity
Prim
ary
outc
ome:
O
S. S
econ
dary
ou
tcom
e: P
FS,
RR
, and
toxi
city
OS
and
PFS
of t
he c
ontro
l ar
m a
re h
ighe
r tha
n ex
posu
re a
rm (P
<0.0
8).
Com
mon
PLD
‑ass
ocia
ted
toxi
city
obs
erve
d ar
e ne
utro
peni
a (1
4%),
thro
mbo
cyto
peni
a (7
%),
anem
ia (1
%),
hand
‑foot
sy
ndro
me
(5%
), m
ucos
itis
The
patie
nt h
ad b
een
treat
ed b
y dr
ugs
othe
r th
an d
oxor
ubic
in. H
ence
, it
is im
porta
nt to
und
erlin
e th
at c
o‑in
terv
entio
n m
ight
in
terfe
re th
e re
sults
. Oth
er
limita
tions
men
tione
d in
th
e ar
ticle
incl
ude
smal
l sa
mpl
e si
ze, l
ong
enro
llmen
t tim
e an
d se
lect
ion
bias
And
ers
et a
l.[22]
Unk
now
n se
tting
s46
tum
or‑b
earin
g m
ice
follo
win
g in
ocul
ated
in
trace
rebr
ally
with
M
DA
‑MB
‑231
‑BR
‑ lu
cife
rase
‑ ex
pres
sing
cel
ls
Labo
rato
ry s
tudy
PLD
ver
sus
nonl
ipos
omal
do
xoru
bici
n
PK
and
effi
cacy
In c
ompa
rison
to
nonl
ipos
omal
dox
orub
icin
, P
LD p
rom
otes
bet
ter e
ffica
cy
and
PK
pro
file
in te
rms
of O
S
and
AU
C in
the
treat
men
t of
intra
cran
ial b
reas
t can
cer
Furth
er e
xam
inat
ion
is
requ
ired
in h
uman
set
ting
Cont
d...
Ngan and Gupta: Liposomal and nonliposomal formulations of doxorubicin
8 Archives of Pharmacy Practice Vol. 7 Issue 1 Jan‑Mar 2016
Tabl
e 1:
Con
td...
Stud
ySe
tting
Part
icip
ants
and
fo
llow
‑up
Stud
y de
sign
Inte
rven
tion
eval
uate
dM
ain
outc
omes
Find
ings
Lim
itatio
ns
Bos
etti
et a
l.[23]
Eur
opea
n co
untri
es15
3 pa
tient
s w
ith re
curr
ent
or p
rogr
essi
ve
ovar
ian
canc
er
Cos
t‑effe
ctiv
enes
s an
alys
is b
ased
on
the
data
of a
n R
CT
PLD
ver
sus
gem
cita
bine
Cos
ts a
nd Q
ALW
sPL
D h
as a
hig
her d
rug
cost
than
gem
cita
bine
. (€
2814
.13
vs. €
1528
.85;
P<
0.00
05).
The
hosp
italiz
atio
n co
st o
f gem
cita
bine
is h
ighe
r th
an P
LD. (
€400
8.80
vs.
€1
394.
38; P
<0.0
005)
. Th
e O
S is
com
para
ble
for
both
gro
ups
(56
wee
ks
for P
LD v
s. 5
1 w
eeks
for
gem
cita
bine
; P=0
.048
). Th
e co
st‑e
ffect
iven
ess
of P
LD w
as
€170
and
€31
8 pe
r QAL
W
whi
le th
e co
st‑e
ffect
iven
ess
of g
emci
tabi
ne w
as
betw
een
€317
and
€58
9 pe
r qu
ality
‑adj
uste
d lif
e w
eek
It is
unc
erta
in th
at th
e sa
me
cost
will
app
ly
to o
ther
cou
ntrie
s
Vici
et a
l.[24]
4 on
colo
gic
cent
ers
of
the
Gru
ppo
Onc
olog
ico
Italia
M
erid
iona
le.
Mar
ch 2
003‑
N
ovem
ber
2005
104
patie
nts
with
hi
stol
ogic
ally
co
nfirm
ed a
dvan
ced
brea
st c
ance
r who
ar
e no
t pre
viou
sly
treat
ed w
ith a
djuv
ant
anth
racy
clin
es
RC
TE
PI/V
and
PLD
/VE
ffica
cy a
ccor
ding
to
RE
CIS
T cr
iteria
an
d to
xici
ty
acco
rdin
g to
Nat
iona
l C
ance
r Ins
titut
e C
omm
on T
oxic
ity
Crit
eria
(ver
sion
3.0
)
3 co
mpl
ete
resp
onse
(5.6
%)
and
20 p
artia
l re
spon
ses
(37%
), fo
r an
over
all R
R o
f 42
.6%
(95%
CI,
29.3
‑55.
9)
in E
PI/V
and
8 c
ompl
ete
resp
onse
s (1
6%) a
nd 1
8 pa
rtial
resp
onse
s (3
6%),
for
an o
vera
ll R
R o
f 52%
(95%
C
I, 38
.2‑6
5.8)
in P
LD/V
. In
term
s of
toxi
colo
gy,
both
arm
s sh
owed
a
tole
rabl
e ad
vers
e ef
fect
No
allo
catio
n co
ncea
lmen
t in
dica
tes
the
risk
of s
elec
tion
bias
. No
blin
ding
indi
cate
s th
e ris
k of
per
form
ance
bia
s
Oso
ba e
t al.[2
5]25
cen
ters
in
Can
ada.
200
125
8 m
ale
patie
nts
with
bio
psy‑
prov
en
AID
S‑r
elat
ed K
apos
i’s
sarc
oma
RC
TP
LD o
r dox
orub
icin
pl
us b
leom
ycin
plu
sP
lus
vinc
ristin
e
Cha
nge
in H
RQ
L fro
m b
asel
ine
to
end
of tr
eatm
ent
rela
ted
to g
ener
al
heal
th, p
ain,
soc
ial
func
tioni
ng, m
enta
l he
alth
, cog
nitiv
e fu
nctio
ning
, en
ergy
/fatig
ue,
heal
th d
istre
ss,
heal
th tr
ansi
tion,
and
ov
eral
l QL
The
patie
nts
treat
ed w
ith
PLD
had
hig
h st
atis
tical
ly
sign
ifica
nt im
prov
emen
t on
4 of
the
9 do
mai
ns (P
<0.0
1),
whi
ch in
clud
es p
ain,
co
gniti
ve fu
nctio
ning
, soc
ial
func
tioni
ng a
nd h
ealth
di
stre
ss. T
he p
atie
nts
treat
ed w
ith d
oxor
ubic
in p
lus
bleo
myc
in p
lus
vinc
ristin
e ha
d de
terio
rate
d en
ergy
and
ex
perie
nced
fatig
ue
No
allo
catio
n co
ncea
lmen
t in
dica
tes
the
risk
of s
elec
tion
bias
. No
blin
ding
indi
cate
s th
e ris
k of
per
form
ance
bia
s.
Add
ition
ally,
he
stud
y w
as
cond
ucte
d on
200
1, w
hich
m
ay n
ot re
pres
ent t
he la
test
ac
tual
ity
Cont
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9Archives of Pharmacy Practice Vol. 7 Issue 1 Jan‑Mar 2016
thought to be closely associated with the hormone. As hormone plays a key role in the immunosuppressive and immunostimulatory activity, the reason behind this observation can be rationalized.[28] There are many factors contributing to the immune status of individuals, indicating the dramatic interpatient variability of liposomal doxorubicin.
Other factors contributing to interpatient variability of PLD are body fat composition and genetic viability.[12] The phenomenon of significantly increased AUC of PLD as a result of high intraabdominal fat content had been observed. In terms of genetic viability, higher VD and CL rate had been detected in Asian in comparison to European.[16]
EFFICACY
The efficacy of the different formulations which involve doxorubicin was evaluated based on response rate, including complete response, partial response, and overall response. The survival rate, which includes overall survival and progression-free survival, is also deemed to be an indicator of efficacy.[6,7,10,13,22,24]
The efficacy of PLD as a single agent in the treatment of metastatic breast cancer has been confirmed. However, there is a lack of scientific consensus that the liposomal formulations of doxorubicin increase the survival rate of the treatment, in comparison to nonliposomal conventional doxorubicin.[6,7,10,13,22,24] Nevertheless, it is clinically significant that PLD decreases the risk of fatal cardiac events such as acute myocardial infarction and congestive heart failure.[6,7,18] As a result, the utilization of PLD increases the survival rate of patients with high cardiac risks compared to nonliposomal conventional doxorubicin.[13,14]
Despite the efficacy of doxorubicin in the treatment of glioma in vitro, its utilization is limited by the efflux effect of the blood-brain barrier (BBB).[15,22] Fortunately, the development of liposomal doxorubicin allows penetration of doxorubicin into the malignant glioma cells in the brain.[15] In spite of the fact that PLD shows high potency in the treatment of glioma, its dosing regimen in children remains unclear. Hence, further studies are necessary to balance the toxicology profile and efficacy of PLD in the treatment of glioma.
Moreover, there are some discrepancies regarding the potency between two formulations (Lipo-Dox and Doxil) of PLD.[6] An observational study indicates that Lipo-Dox is inferior to Doxil in terms of potency.[6] However, this observation might not be clinically Ta
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Ngan and Gupta: Liposomal and nonliposomal formulations of doxorubicin
10 Archives of Pharmacy Practice Vol. 7 Issue 1 Jan‑Mar 2016
significant as a larger sample size is needed to confirm the finding.
In addition, laboratory data have showed the efficacy of PLD in the treatment of intracranial model of breast cancer in mice.[22] In this model of breast cancer, PLD promotes higher survival rate and efficacy with reduced toxicity than nonliposomal doxorubicin in mice.[22] Clinical data regarding the utilization of PLD in this model of metastasis breast cancer is eagerly awaiting.
TOXICOLOGY
In comparison to nonliposomal conventional doxorubicin, it is certain that the liposomal formulations of doxorubicin promote better cardiac safety.[7,9-14,19,21] The reduced cardiac toxicity had also been observed in comparison to other anthracycline-based chemotherapy.[14] Therefore, it is recommended that the liposomal formulations of doxorubicin should be used in the patients with high risk of cardiac events such as arrhythmia, congestive heart failure, and myocardial infarction.[13,21]
Furthermore, the reduced toxicity has also been observed in terms of myelosuppression and infection in comparison to nonliposomal conventional doxorubicin.[10] However, the myelotoxicity of liposomal doxorubicin is not uncommon.[7,12] The myelotoxic effects in association with liposomal doxorubicin include leukopenia, neutropenia, thrombocytopenia, and febrile neutropenia.[7,9-14,19]
In terms of extra-myelotoxicity other than cardiotoxicity, the occurrence of Palmar-Plantar Erythrodysesthesia (commonly known as a hand-foot syndrome) is similar in both liposomal and nonliposomal formulations of doxorubicin.[9,11,21] Nausea and vomiting are moderate to severe in patients treated with nonliposomal doxorubicin but are usually mild in patients treated with liposomal doxorubicin.[3,19]
As the liposomal formulations of doxorubicin undergo viability in relation to PKs, dose-dependent myelotoxicity cannot be effectively predicted.[7,9-14] Factors affecting the PKs of liposomal doxorubicin are likely to affect the toxicology profile of such formulations. In general, higher risk of toxicity is expected to be seen in elderly patient, immunosuppressive” and female individuals.[8] Patients with high body fat composition, particularly
intraabdominal fat, are also more susceptible to experience doxorubicin-associated myelotoxicity if they are treated with liposomal doxorubicin.[12]
Under the extremely rare scenario, acute peculiar mucous reaction following administration of PLD had been reported.[29] No study had been conducted in this area as the occurrence of this reaction had not been observed prior to the case report. Hence, further study has to be carried out in this area.
QUALITY OF LIFE AND COST‑EFFECTIVENESS ANALYSIS
Although the improved survival rate with the use of liposomal doxorubicin has not been proven, it is observed that the patients receiving liposomal doxorubicin have a higher quality of life than the patients treated with nonliposomal doxorubicin in terms of pain, cognitive functioning, social functioning, and health distress.[21,25] The improved quality of life is believed to be associated with the decreased adverse drug effects and the elevated selectivity promoted by the liposome in the liposomal formulation of doxorubicin.
However, the improved quality of life other than nausea and vomiting related to liposomal doxorubicin has not been detected in elderly patients with metastatic breast cancer.[19] This phenomenon can be explained by the deteriorated immune system of the elderly patients, resulting in a significant decrease in the CL of liposomal doxorubicin.[28] Consequently, a significant increase in AUC accounts for the dose-dependent toxicity following the administration of liposomal doxorubicin.[11]
Since the utilization of liposomal doxorubicin reduces the severity of chemotherapy-induced nausea and vomiting (CINV) in conjunction with the treatment of nonliposomal conventional doxorubicin, it is deemed to reduce the direct cost related to the CINV. As the CINV had been highlighted to be a significant cost to the National Health Service in European countries, the possibility of cost reduction is clinically significant.[17] Nonetheless, further investigation is needed to confirm the actuality of this extrapolation.
Regarding the routine cardiac surveillance prior to PLD treatment, it is believed to be unnecessary as selective cardiac surveillance will save more than 180,000 USD in 184 patients received PLD.[26] However, as PLD is 100-times more costly than conventional
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11Archives of Pharmacy Practice Vol. 7 Issue 1 Jan‑Mar 2016
nonliposomal doxorubicin, it is debatable that an opportunity of saving more than 4,400,000 USD will be ignored if practicing selective cardiac surveillance.[30]
As there is a lack of updated primary sources comparing the cost-effectiveness of liposomal doxorubicin and nonliposomal conventional doxorubicin, the cost-effectiveness studies comparing liposomal doxorubicin with other nonliposomal anticancer drugs have been included. The assumption being made is that similar result will be expected in nonliposomal conventional doxorubicin in comparison to other nonliposomal anticancer drugs as they belong to the class of chemotherapy whereas liposomal doxorubicin belongs to the class of nanotherapy.
In comparison to anticancer drugs other than doxorubicin, PLD has a higher efficacy and cost than gemcitabine, the incremental cost-effectiveness ratio (ICER) observed for PLD was between €170 and €318 per QALW, which is between €8864 and €16581 per quality-adjusted life year (QALY) gained.[23] In terms of paclitaxel, PLD possesses higher efficacy and cost, with an ICER of 21,658 USD per QALY gained.[20] Overall, PLD is deemed to be cost-effective in some most countries, referring to the willingness-to-pay (WTP) threshold recommended by World Health Organization (WHO).[31] However, based on the gross domestic product stated by WHO, PLD may not be cost-effectiveness in some developing countries.[31]
DISCUSSION AND CLINICAL IMPLICATION
This review highlights the clinical significance of the interpatient variability associated with the use of liposomal doxorubicin. It is impacted by age, gender, race, immune status, and body fat composition of an individual treated with liposomal doxorubicin.[8,9,12] An important clinical concern is that most cancer patients are middle-aged or elderly, indicating a need for dose adjustment in the treatment of liposomal doxorubicin. Otherwise, the dose-dependent toxicity associated with liposomal doxorubicin cannot be extrapolated and managed. However, the effective way of individualizing the dose of liposomal doxorubicin has not been identified.
In the near future, the liposomal doxorubicin will be prescribed in more conditions such as pediatric glioma and intracranial model of breast cancer as the utilization of the liposome brings about the penetration across BBB.[15,22] As the PK model of the
liposomal doxorubicin in children remains unclear, more comprehensive precautions will be required to prevent or manage the adverse drug reaction of the liposomal doxorubicin in this population. Concerning the intracranial model of breast cancer, further studies are needed to investigate how the liposomal doxorubicin behaves in human settings.[22]
In terms of efficacy, there is limited evidence base to support the superiority of the liposomal doxorubicin compared to the nonliposomal conventional doxorubicin.[6,7,10,13,22,24] Nevertheless, stringent precautions are recommended before choosing a formulation of doxorubicin for high-risk patients to protect against fatal cardiac events, as the reduced cardiotoxicity promoted by the liposomal doxorubicin has been confirmed. Subsequently, the clinical concern aroused is the cost-effectiveness of the routine cardiac surveillance prior to the introduction of liposomal doxorubicin. Overall, there remains a considerable controversy over the relative importance of routine cardiac surveillance in the patients accepting doxorubicin-based therapy.
Although the updated cost-effectiveness of the liposomal doxorubicin compared to nonliposomal doxorubicin remains unclear, the cost-effectiveness of liposomal doxorubicin in comparison to other chemotherapy is within the Willingness to Pay (WTP) threshold in most developed countries, so that the use of liposomal doxorubicin is deemed to be cost-effective only in this particular countries.[20,23,31] In healthcare settings, liposomal doxorubicin is considered to be more tolerable than nonliposomal conventional doxorubicin as regards of cardiotoxicity, myelotoxicity, nausea and vomiting with an estimation of 100 times the additional cost. Therefore, further pharmacoeconomic studies comparing liposomal and nonliposomal formulations of doxorubicin will be required to confirm the cost-effectiveness of liposomal doxorubicin.
In addition, this review reveals some limitations and weaknesses in relation to the updated evidence. The lack of blinding and allocation concealment in the randomized control trials could probably lead to a bias toward the superiority of liposomal formulation of doxorubicin compared to nonliposomal conventional doxorubicin. Another common weakness in most of the literature is the underpowered sample size. Therefore, it is identified that the sample present in the studies may not represent the whole population. Hence, larger studies are required to confirm the actuality
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12 Archives of Pharmacy Practice Vol. 7 Issue 1 Jan‑Mar 2016
of the results. Notwithstanding, the contamination, and co-intervention in most of the studies are well controlled, indicating that the results could be statistically and clinically significant. Further, our review did not compare the efficacy and toxicology of liposomal doxorubicin with other marketed chemotherapy, which is thought to be closely related to the current healthcare settings.
CONCLUSION
In summary, there remains a substantial gap in the scientific literature on the superiority of liposomal doxorubicin in relation to efficacy. While there is some experimental evidence that liposomal doxorubicin is able to increase survival rate in mice having an intracranial model of breast cancer, there is less evidence on its efficacy in healthcare settings. Current research has several limitations including the possibility of selection bias and performance bias as well as underpowered samples. However, it is confirmed that PLD and non-PLD encompass better safety profile compared to nonliposomal conventional doxorubicin in terms of cardiotoxicity and myelosuppression. However, larger interpatient variability in terms of PK is common in liposomal doxorubicin resulting in the difficulty in dose standardization. Moreover, the utilization of liposomal doxorubicin in the treatment of brain tumor will be developed in the near future. Large intervention studies in this area are likely to provide the best evidence of the efficacy of liposomal doxorubicin in increasing the survival rate in comparison to nonliposomal conventional doxorubicin. Finally, dose standardization is an urgent priority to manage the doxorubicin-induced toxicity following the administration of liposomal doxorubicin.
Financial support and sponsorshipNil.
Conflicts of interestThere are no conflicts of interest.
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