Amphotericin B is a polyene macrolide derived
from Streptomyces nodosus. Introduced into therapy
in 1957, for decades amphotericin B has been the
“gold standard” for fighting systemic fungal infec-
tions (1, 2).
This drug exerts a fungistatic or fungicidal effect
according to the concentration reached in body fluids
and the susceptibility of the fungus. In order to facili-
tate its use in the treatment of fungal infections, much
attention has been paid to the development of phar-
maceutical forms that could reduce its toxicity, espe-
cially for the kidney. Because of its low solubility in
water and excellent solubility in lipids,amphotericin B
is an ideal candidate for lipid-based formulations (3).
There are currently four commercially available for-
mulations of amphotericin B:
• Amphotericin deoxycholate (Fungizone®). In
water it forms a colloidal suspension with parti-
cles of diameter less than 0.4 µm.
• Liposomal amphotericin (AmBisome®)
• Amphotericin lipid complex (Abelcet®)
• Amphotericin colloidal dispersion (Amphocil®)
AmBisome®, Abelcet® and Amphocil® are lipid
formulations for intravenous infusion, whose prepara-
tion was possible due to the amphipathic nature of
Commercially available lipid formulations of amphotericin
B:are they bioequivalent and therapeutically equivalent?
Carlo Cifani1, Sarah Costantino2, Maurizio Massi1, Liberato Berrino2
1School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino, Italy;2Department of Experimental Medicine,
Pharmacology Division, Second University of Naples, Naples, Italy
Abstract. Amphotericin B is a polyene macrolide derived from Streptomyces nodosus. Introduced into thera-
py in 1957, for decades amphotericin B has been the “gold standard” for fighting systemic fungal infections.
In order to facilitate its systemic use, much attention has been paid to the development of pharmaceutical
forms that could reduce its toxicity, especially for the kidney. Because of its low solubility in water and ex-
cellent solubility in lipids, amphotericin B is an ideal candidate for lipid-based formulations.Three different
lipid formulations for intravenous infusion are currently commercially available: liposomal amphotericin
(AmBisome®),Amphotericin lipid complex (Abelcet®) and Amphotericin colloidal dispersion (Amphocil®).
The three lipid formulations of amphotericin B show significantly different structural, physical, chemical,
pharmacokinetic, pharmacodynamic and toxicological characteristics. Several lines of evidence indicate that
the three formulations of amphotericin B are not therapeutically equivalent.First,they are not bioequivalent.
Second,even though a complete picture of controlled clinical research designed to compare effectiveness and
safety of the three lipid formulations is not available, all the clinical studies analyzed report clear differences
in toxicity between the three formulations. AmBisome® appears to be clearly less toxic than the other two
formulations, in terms of nephrotoxicity and of incidence of infusion-related adverse events.Third, the ther-
apeutic non-equivalence of the three lipid formulations of amphotericin B is further supported by statements
of Conferences and Scientific Societies that in their recommendations have awarded different grading to the
three lipid formulations. (www.actabiomedica.it)
Key words:Amphotericin B, Lipid amphotericin formulations, AmBisome®, Abelcet®, Amphocil®
U PT O D A T E
ACTA BIOMED 2012; 83: 154-163 © Mattioli 1885
Lipid formulations of amphotericin B
2. Physical and chemical properties
AmBisome® is a lyophilised formulation con-
taining amphotericin B in combination with lipids in
a molar ratio of about 10% (4). It is incorporated into
unilamellar liposomes with a diameter of 60-70 nm,
thus it may be considered as a kind of special colloidal
system (Fig. 1).The liposomes are made up of hydro-
genated soybean phosphatidylcholine, cholesterol and
distearoyl phosphatidylglycerol in a ratio of 10:5:4 (5).
The stability of the liposome is ensured by the fact
that cholesterol and distearoyl phosphatidylglycerol
exhibit a high transition temperature (55°C), close to
which the lipid preparation naturally tends to collapse,
releasing its contents (3).The stability of the liposome
is also guaranteed by its small size.Moreover,the neg-
ative charge of distearoyl phosphatidylglycerol can in-
teract with the positive amino group of amphotericin
B to form an ion complex in the lipid bilayer (4).
Abelcet® is a lipid complex of amphotericin B. It
consists of two phospholipids in a molar ratio of 1:1
with the drug. The two phospholipids, L-α-dimyris-
toyl phosphatidylcholine and dimyristoyl phos-
phatidylglycerol, are present in a ratio of 7:3 (6). Un-
like the liposomal formulation,Abelcet® has a ribbon-
like appearance due to rupture of the lipid bilayer
caused by amphotericin B, and to reorientation of the
lipids and amphotericin B to form ribbon-like struc-
tures larger than 1600 nm (Fig. 1). Both phospho-
lipids have a transition temperature of 23 °C, which is
below body temperature; this means that the lipid
complex may disintegrate before reaching the site of
Amphocil® is made up of amphotericin and sodi-
um cholesteryl sulfate in a 1:1 ratio. It is a colloidal
dispersion with a disc-like structure. Each disc has an
approximate diameter of 122 nm and a thickness of 4
nm (Fig. 1) (7).
3. Pharmacokinetic properties AmBisome®
AmBisome® is made up of small, rigid and
spherical liposomes, that are taken up slowly by the
reticulo-endothelial system (8). Studies with single-
dose AmBisome® in rats and mice have shown greater
plasma concentration, a longer elimination half-life
and a larger AUC than conventional amphotericin.
Moreover, studies with multiple doses have highlight-
ed that the active ingredient is concentrated more in
the spleen and in the liver, whereas concentrations in
the kidney and lungs (Table 1) are similar to those
found after administration of Fungizone® (9). The
uptake of intact liposomes by the liver is rather slow,
leading to a slow decline in liposome blood levels (10).
Clinical trials have been carried out using AmBi-
some®. At a dose of 5 mg/kg, plasma concentration
reaches a peak of 83 mg/l. This concentration, as
shown in Table 2, is 25-200 times higher than that of
Abelcet® and Amphocil® administered at the same
dose. The Cmax for amphotericin B after AmBisome®
administration reaches mean values around 26 and 48
times higher than those obtained after administration
of Abelcet® and Amphocil®, respectively (11, 12).
A phase IV study performed on healthy volun-
teers highlighted that AmBisome®,compared to Fun-
gizone®, Amphocil®, Abelcet® leads to a higher plas-
ma concentration and a lower Vd. (13).There was al-
so a marked decrease in the excretion of unchanged
amphotericin B in urine and feces (14).This could be
the reason for the lower incidence of nephrotoxicity
with AmBisome® (15).
The passage of amphotericin B into brain tissue
also occurred in the presence of intact meninges, and
C. Cifani, S. Costantino, M. Massi, L. Berrino
tissue concentrations after administration of AmBi-
some® were found to be 6-10 times higher than those
of Abelcet® and Amphocil®.
Finally, after a single intravenous administration,
AmBisome® led to a far higher amphotericin B con-
centration in the aqueous humor of an inflamed eye
than with Abelcet® and Fungizone®.
Preclinical trials have shown that Abelcet® is tak-
en up rapidly and in significant quantities by mononu-
clear phagocytes of the reticulo-endothelial system.
This results in a concentration of amphotericin B in
the systemic circulation in human subjects that is 5
times lower than when using Fungizone®, with plas-
ma peaks of no more than 5 mg/ml when adminis-
tered at therapeutic doses (1-10 mg/kg) (16, 17).
Pharmacokinetic studies with Abelcet®have shown a
lower AUC0-24 than for Fungizone®. The Vd and
clearance are 3 and 7 times higher, respectively, than
those for Fungizone® (10). Further studies, conducted
using multiple doses in animals, showed a dose-de-
pendent increase in the concentrations of ampho-
tericin B in the liver, spleen and lungs (5).
In a study in mice with pulmonary aspergillosis,
both AmBisome® and Abelcet® administered at dos-
es of 1, 4, 8 or 12 mg/kg resulted in lung concentra-
tions above therapeutic levels (3 g/g), but lung levels
of Abelcet® were still high.In response to a dose of 12
mg/kg, both formulations produced a survival rate of
57%, but at higher doses (15-20 mg/kg) survival rates
in animals treated with AmBisome® rose to 80-90%,
while that of animals treated with Abelcet® were in-
distinguishable from that of the controls. At these
doses, Abelcet® showed clear nephrotoxicity, while
AmBisome® gave renal function parameters similar to
those of controls (18).
A study by Fielding et al., (16) showed that Am-
phocil®, administered to rats at a dose of 5 mg/kg,
causes a lower peak plasma concentration and the
AUC is 2 times less than for Fungizone®.The Vd and
clearance, by contrast,are higher for Amphocil®.Am-
phocil® is rapidly cleared from plasma and taken up
mainly by the tissues of the reticulo-endothelial sys-
tem, with plasma peaks of no more than 5 mg/ml
when administered at therapeutic doses (1-10 mg/kg)
Table 1. Distribution of the three lipid formulations of amphotericin B
Tissue concentration of amphotericin
compared with conventional amphotericin
Abelcet®Lower HigherHigher Similar
AmBisome®Higher Higher SimilarSimilar
From Metha J (10)
Table 2. Pharmacokinetic parameters of the three lipid formulations of amphotericin B
FormulationSize (nm) StructureDose (mg/Kg)Cmax(mg/l) AUC (mg·h/l)Vd(l/kg)
From Dupont B. (11)
Lipid formulations of amphotericin B
(16, 17). AUC, Cmaxand Vd values appeared to be in-
termediate compared to those for AmBisome® and
Abelcet® administered at the same doses (Table 2).
As far as distribution is concerned, the highest
tissue concentrations were found in the liver, spleen
and bone marrow. The high concentrations of Am-
phocil® in the liver were caused by the rapid and ex-
tensive uptake by the liver phagocytic cells.Therefore,
it has been proposed that the liver may act as a reser-
voir of lipid-complexed amphotericin from which the
active ingredient is slowly released (16). Moreover, its
small size enables Amphocil® to cross the pulmonary
vascular bed without accumulating there (19). The
concentration of amphotericin in other organs,such as
the kidney and heart, is comparable to those found af-
ter administration of Fungizone® (20). The concen-
trations observed in the kidney were three times high-
er after Amphocil® than after AmBisome® (21).
4. Pharmacodynamic properties and mechanism of
The exact mechanism of action by which ampho-
tericin B contained in AmBisome® penetrates the
fungal cell has not yet been clarified. It has been sug-
gested that amphotericin B activity is due to the high
binding affinity of amphotericin B for ergosterol, the
main component of the plasma membrane in fungi.
Amphotericin B molecules form a rosette pattern
around ergosterol, leading to a structural modification
of the membrane,with pore formation.The pores lead
to the formation of channels through which compo-
nents of the fungal cell can leak, thus altering the os-
motic integrity of the cell and causing its death. Inhi-
bition of the proton ATPase in the fungal cell mem-
brane and inhibition of lipid peroxidation are addi-
tional cytotoxic mechanisms of amphotericin B (22).
Amphotericin B has a concentration-dependent
type activity, i.e. primarily related to the concentration
at which it reaches the fungal cell. For a Cmax/MIC ra-
tio of 4, amphotericin B is already clearly effective,
and its efficacy becomes optimal at a ratio of 10 (22,
23). Since the activity of amphotericin B is concentra-
tion-dependent, it should be administered once daily
by infusion, whose duration (3-4 hours for deoxy-
cholate and 2 hours for AmBisome®) is conditioned
by the toxicity of the formulation used.
The concentration-dependent effect is also asso-
ciated with a post-antifungal effect (PAFE), i.e. repli-
cation of the fungus remains suppressed even when
the drug concentration has fallen below the MIC.
Amphotericin B has a significant PAFE, higher than
that of echinocandins;triazoles are not associated with
PAFE (3). The onset of resistance to amphotericin B
is unlikely (24).
In AmBisome®, amphotericin B is closely inte-
grated with the liposome membranes forming a non-
covalent complex between amphotericin B my-
cosamine (positively charged) and distearoyl phos-
phatidylglycerol (negatively charged),as well as by hy-
drophobic interactions with the cholesterol membrane
(12). The stability of the formulation does not affect
its efficacy. Experiments with the dye sulforhodamine
have shown that liposomes accumulate at the site of
infection by adhering to the surface of fungal cells
even when they lack amphotericin B (25, 26). In fun-
gal cells the liposome disintegrates and releases am-
photericin B, which can thus exert its antifungal ac-
tion at the site of infection (25).
The mechanism proposed for Abelcet® is differ-
ent. In fact,it is assumed that fungal lipases play a cru-
cial role by acting on the lipid formulation to induce
release of Amphotericin B into the tissues (27). For
Amphocil®, by contrast, it is suggested that the prod-
uct is taken up by the phagocytic cells of the liver
which then release processed amphotericin B into the
circulation (20). In particular, macrophages can func-
tion as reservoirs of amphotericin B, due to their in-
tracellular and extracellular antimicrobial activity. In
this regard, Mehta et al. (10) showed that the im-
provement in the anti-candidiasis activity of AmBi-
some® is not due to the activation of macrophages. It
seems that the improvement in anti-candidiasis activ-
ity depends on the increased uptake and retention of
AmBisome® and its slow release by the macrophages.
Indeed, AmBisome® is ingested by macrophages (28,
29) or monocytes and slowly processed and released to
carry out its intra- ed extra-cellular antimicrobial ac-
tivity. The speed with which AmBisome® is released
by the macrophages is influenced by the stability of
the complex (30).
C. Cifani, S. Costantino, M. Massi, L. Berrino
Amphotericin B also shows affinity, although
lower, for the cholesterol of human cell membranes;
this property is at the basis of its potential toxicity.
Boswell et al. (12) reported that AmBisome® li-
posomes damage the membranes of erythrocytes to a
far lesser extent than Amphocil® and Abelcet®. On in
vitro erythrocytes, amphotericin B damages the mem-
brane, releasing potassium and hemoglobin into the
medium. The different formulations of amphotericin
B were incubated with erythrocytes for 4 hours at 37°.
The release of potassium into the medium was caused
by low concentrations of Fungizone®. Amphocil® and
Abelcet® required higher concentrations; AmBi-
some® required concentrations 3-4 times higher than
those of Abelcet® and Amphocil® to cause leakage of
potassium into the medium.
The fact that amphotericin B is retained by the
liposomal dosage form until the site of infection is
reached reduces the risk of nephrotoxicity related to
high cholesterol content in renal tubular cells.
On the other hand, AmBisome® liposomes re-
main intact in the plasma for about 24 hours, allowing
them to continuously affect the properties of the am-
photericin B that they contain.
6. Clinical efficacy trials
In vitro, the order of antifungal activity is Fungi-
zone® > Abelcet® > Amphocil® > AmBisome® (31,
32). Studies carried out in vitro do not take into ac-
count the different pharmacokinetic distribution of
amphotericin B in the various formulations and do
not correspond to the results obtained in vivo (33).
Ostrosky-Zeichner et al.(1) examined several
clinical trials which highlighted that all of the new
formulations of amphotericin B were more efficacious
than Fungizone®. So the comparison between the ef-
ficacy of the different formulations of amphotericin B
is subject to debate. In a very recent article, Bellmann
(2) reports that AmBisome® was compared with Fun-
gizone® in two randomized clinical trials and as em-
pirical therapy for a multicenter randomized trial in
687 patients with persistent fever and neutropenia.
The therapeutic efficacy of AmBisome® was similar
to that of Fungizone®, while both nephrotoxicity and
the incidence of infusion-related adverse events were
significantly lower after administration of AmBi-
The treatment of fungal infections is not easy, as
most of the organs generally appear to be infected and
patients often have concurrent diseases.
In order to compare the activity of various for-
mulations of amphotericin B, it would be interesting
to evaluate the various pharmacokinetic characteristics
of the lipid formulations related to their clinical effi-
cacy. In this regard, it is important to focus attention
on the target organs of amphotericin B, which are the
main target of the pathogens.
In patients with disseminated candidiasis,it would
be logical to state that AmBisome®, which has the
highest elimination half-life (35),could be more effica-
cious than the other formulations of amphotericin B.
In fact, Linder et al. (36) reported that clearance of
fungemia was obtained in 83% of patients receiving
AmBisome®, in 57% of subjects treated with Am-
phocil® and 68% of patients treated with Fungizone®.
Treatment with AmBisome® and Abelcet®
shows that response rates in aspergillosis are much
higher than with Fungizone® (1, 37, 38). The prefer-
ential localization of amphotericin B in the lungs and
the high doses of Abelcet® and AmBisome® adminis-
tered compared to those of Fungizone® may explain
the difference in efficacy.
In Cryptococcus infections, in which the CNS is
the primary site of infection, AmBisome® has a sig-
nificantly greater effect than Fungizone® (39).Anoth-
er study highlighted the greater efficacy of Abelcet®
(86%) compared to Fungizone® (65%) (40).
Recently, AmBisome® was registered for the
treatment of visceral leishmaniasis (in which the par-
asite localises preferentially at the level of the reticulo-
endothelial system), and a single dose of 5 mg/kg
proved to be sufficient to treat 90% of patients in a
clinical study performed in India (41, 42). Other lipid
formulations of amphotericin B have been shown to
have similar efficacy, although multiple doses are re-
quired (43, 44).
AmBisome® has been compared to Abelcet® for
the empirical treatment of febrile neutropenia (45).
Lipid formulations of amphotericin B
Although the two formulations have similar efficacy,
AmBisome® was associated with significantly lower
toxicity and therefore fewer patients receiving AmBi-
some® discontinued the therapy.Several studies report
that Amphocil® has antifungal efficacy similar to that
of Fungizone®, but that the toxicity of the latter was
significantly higher than that of Amphocil® (2).
Lanternier and Lortholary (46) report the results
of several retrospective studies on the survival of pa-
tients with zygomycosis treated with one of the three
lipid formulations of amphotericin B. The survival
rate was 69% with AmBisome®, 75% with Abelcet®,
60% with Amphocil®, and 61% with Fungizone®.
Finally, Moen et al. (47) report that liposomal
amphotericin B remains the first-line option for em-
pirical therapy in patients with febrile neutropenia and
in those with disseminated histoplasmosis and an op-
tion for AIDS-associated cryptococcal meningitis and
invasive Candida and Aspergillus infections. In com-
parison with other amphotericin B formulations,
treatment with liposomal amphotericin B is associat-
ed with a lower incidence of infusion-related adverse
reactions and with reduced nephrotoxicity in response
to a standard dose of 3 mg/kg/day.
7.Tolerability and safety studies
The main problem of amphotericin B is its po-
tential toxicity, in particular its nephrotoxicity, and in-
fusion-related adverse reactions, such as chills, stiff-
ness, fever and hypoxia. In this regard, several authors
have argued that the choice of amphotericin B dosage
form should be primarily based on its toxicological
In 1995, Arning had already shown that AmBi-
some® infusion induces fewer adverse events than
Abelcet® and Amphocil®, attributing this difference
to the lower release by AmBisome® of cytokines.
These formulations led to significant infusion-related
adverse events, and resulted in a significant increase in
plasma levels of IL-6 and IL-8, although to a lesser
extent than IL-6 (51, 52).
Lipid formulations show less nephrotoxicity than
Fungizone®. In a multicenter double-blind clinical
study (34), 687 patients were randomized to receive
either AmBisome® or Fungizone® as empirical thera-
py for persistent fever and neutropenia. Similar out-
comes were observed in terms of survival and resolu-
tion of fever. But AmBisome® was associated with
lower nephrotoxicity and fewer infusion-related ad-
verse events. Probably, AmBisome® has less adverse
events because the concentration of Amphotericin B
in this formulation is lower (1). An important role in
the induction of nephrotoxicity is the different state of
aggregation of amphotericin B. The amphotericin B
in Fungizone® is in an oligomeric state, which is the
most cytotoxic, while the lipid formulations contain
less toxic aggregates.
Furthermore, AmBisome® is less toxic than
Abelcet® (11). In fact, a randomized double-blind
study clarified that nephrotoxicity, assessed on the ba-
sis of a doubling of serum creatinine, is significantly
higher for Abelcet® at both 3 and 5 mg/kg/day than
for AmBisome® (53). Moreover, Abelcet®, unlike
AmBisome®, causes a significant number of adverse
events such as chills and shivering, fever, hypoxia and
other infusion-related reactions (Table 3).
Various studies have shown that AmBisome® has
a better profile in terms of reactions during the first
Table 3. Reactions related to the first day of infusion for Abelcet® and AmBisome®
Reactions Percentage of patients
Fever (increase = 1°C)
From Dupont B. J Antimicrob Chemother 2002; 49, suppl S1: 31-36 (11)
C. Cifani, S. Costantino, M. Massi, L. Berrino
day of infusion (11) . In a recent prospective study in
immunocompromised patients conducted in 20 Euro-
pean centers (LEAD I), it was noted that the various
formulations of amphotericin B exert a strong influ-
ence on nephrotoxicity, which was associated with
longer duration of hospitalization (54) and higher
One study in 20 subjects died for failure of vari-
ous organs showed concentrations in the kidney and
lungs that were three times higher after Amphocil®
than after AmBisome® (21). Pea (3) suggests that the
risk of nephrotoxicity may be inversely related to ac-
cumulation of the drug in the kidney.
A dose-escalation study (55) with repeated ad-
ministrations of up to 15 mg/kg of AmBisome®
showed better tolerability by patients compared to
Fungizone®, and when administered with other
nephrotoxic drugs such as cyclosporins, AmBisome®
does not significantly increase nephrotoxicity (56).
Furthermore,on the basis of its lower toxicity and
its greater ability to penetrate the brain compared to
the other lipid formulations, AmBisome® was ap-
proved as a drug that, at high doses and repeated ad-
ministrations, can treat brain and other stubborn in-
fections (fusariosis and zygomycosis).
The better tolerability of lipid formulations has
been documented by a meta-analysis study in over
4500 patients (57).The paper reports that discontinu-
ation of antifungal therapy due to toxicity problems is
on average 5-15 times lower for the three lipid formu-
lations, compared to Fungizone®.The three lipid for-
mulations gave rise to much lower nephrotoxicity than
that of Fungizone®. Of the three lipid preparations,
AmBisome® had the lowest nephrotoxicity.
8. Guidelines and recommendations
Scientific Societies in the field have awarded dif-
ferentiated grading to the various lipid formulations of
The recommendations of the First European
Conference on Infections in Leukaemia (ECIL-1),
for empirical treatment in neutropenia patients, dis-
tinguish between AmBisome®, Abelcet® and Fungi-
As regards treatment for invasive aspergillosis,
the ECIL attributed level BI for AmBisome®, BII for
Abelcet®, and DI for Fungizone® and Amphocil®.
On the other hand, for the treatment of invasive
aspergillosis, the most recent guidelines of the Infec-
tious Diseases Society of America (IDSA) report that
“liposomal amphotericin B can be considered as alter-
native first-line therapy in some patients (A-I)” (58).
The recommendations from the Second ECIL
Conference are also different for AmBisome® in rela-
tion to other lipid formulations of amphotericin B for
treating candidemia in hematological patients prior to
identifying the fungal species involved (Table 4).
Update ECIL-2 2007
It seems evident that the recommendations of au-
thoritative scientific Societies make a clear distinction
between the different lipid formulations of ampho-
tericin B for the purposes of their use in therapy.
In 2009, the IDSA published an Update to the
Guidelines for the treatment of candidiasis, compared
with those previously published in January 2004.
The 2009 Guidelines mention the three different
lipid formulations of amphotericin B: AmBisome®,
Abelcet® and Amphocil®. In this regard, the Guide-
lines indicate that the three formulations have the
same spectrum of activity as Fungizone®, but each of
them presents different pharmacological properties
and frequencies of treatment-related adverse events,
and “should not be interchanged without careful con-
Table 4. Candidemia in hematologic patients before species
Overall populationHematological pts
A I *
A I **
* Not in severely ill patients or in patients with previous azole
** Not in patients with previous azole prophylaxis
Lipid formulations of amphotericin B
In a recent review article (46) the authors argue
that liposomal amphotericin:
1. May be considered first-line treatment for
HIV-positive patients with disseminated histo-
plasmosis and patients with cryptococcal
meningitis,even in the presence of kidney dam-
age or administration of nephrotoxic drugs.
2. In the case of zygomycosis, liposomal ampho-
tericin B is a first-line treatment and high dos-
es are recommended.
3. Liposomal amphotericin B may play a primary
role in the empirical treatment of persistent
4. For invasive aspergillosis, use is recommended
in cases associated with risk of drug interac-
tions and for patients with renal failure or azole
5. Liposomal amphotericin B remains a viable
therapeutic option for treating candidemia and
a cornerstone for the treatment of certain vis-
ceral locations in systemic candidiasis,in partic-
ular in patients with renal impairment or for
concomitant use of nephrotoxic drugs,as well as
in cases of Candida meningitis or endocarditis.
Based on the above considerations and data from
the literature, can it be argued that the three formula-
tions of amphotericin B are bioequivalent and thera-
peutically equivalent to each other?
To answer this question, it must first be remem-
bered that the concept of equivalence is based on three
factors: pharmaceutical equivalence, bioequivalence
and therapeutic equivalence. Two preparations are
considered pharmaceutically equivalent if they have
the same qualitative and quantitative composition of
active ingredients and the same pharmaceutical form.
Two pharmaceutical equivalents are defined as bioe-
quivalent when, following administration of the same
dose, their bioavailability do not differ statistically. If
it is shown that two pharmaceutically equivalent
forms are also bioequivalent, it can be assumed that
they should be also therapeutically equivalent (theory
of therapeutic equivalence).
The pharmacokinetic parameters of the lipid for-
mulations of amphotericin B are markedly different
from those of Fungizone®.
Indeed, AmBisome® is associated with a much
higher amphotericin B AUC than Amphocil® and
Abelcet® (3, 11). The Cmaxof AmBisome® appears to
be much higher than that of the other two lipid for-
mulations. In agreement with these data, the volume
of distribution of AmBisome® is decidedly lower than
that reported for the two other lipid formulations.
Moreover,the data inTable 2 show that the AUC
of amphotericin B for Abelcet® is equal to 1.71% that
of AmBisome®. On the other hand, the AUC for
Amphocil® is equal to 7.74% of that of AmBisome®.
In relation to Cmax, Abelcet® reaches a Cmaxequivalent
to 2.04% compared to AmBisome®,while Amphocil®
reaches a Cmaxequivalent to 3.73% of that of AmBi-
Since the 90% confidence interval for AUC, and
the Cmaxfor the three lipid formulations are both out-
side the range 80-125% (59), the formulations cannot
be considered bioequivalent.
Finally, the three different lipid formulations of
amphotericin B (AmBisome®, Abelcet® and Am-
phocil®) cannot be considered therapeutically equiva-
1. They are not bioequivalent.
2. There is no complete picture of controlled
clinical research designed to compare the ef-
fectiveness of three lipid formulations of am-
photericin B and clinical trials available in the
literature often document similar efficacies be-
tween the different lipid formulations of am-
photericin B, and between lipid formulations
and Fungizone®; only a few studies highlight
greater activity of liposomal amphotericin B.
On the other hand, all of the clinical studies
analyzed report clear differences in toxicity be-
tween the various formulations of ampho-
tericin B. AmBisome® appears to be clearly
less toxic than the other two formulations,
again in terms of nephrotoxicity and of inci-
dence of infusion-related adverse events.
3. The therapeutic non-equivalence of the three
lipid formulations of amphotericin B is further
supported by the fact that in their recommen-
C. Cifani, S. Costantino, M. Massi, L. Berrino
dations Conferences and Scientific Societies
have awarded different grading to the three
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Accepted: 5th July 2012
Correspondence: Liberato Berrino, MD
Department of Experimental Medicine
Second University of Naples
Via Costantinopoli 16, 80138 Naples, Italy