Drug Profile

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Anidulafungin: advantage for

the newcomer?
Expert Rev. Clin. Pharmacol. 1(2), 207216 (2008)

Maria J Rping,
Jrg J Vehreschild,
Fedja Farowski and
Oliver A Cornely

Author for correspondence

Uniklinik Kln, Klinik I fr
Innere Medizin, Klinisches
Studienzentrum,
Schwerpunkt Infektiologie II,
Bachemer Str. 86, 50931
Kln, Germany
Tel.: +49 221 478 6494
Fax: +49 221 478 3611
oliver.cornely@ctuc.de

Anidulafungin is the most recently approved compound of the echinocandin antifungal class.
Its mode of action is the noncompetitive inhibition of (1,3)-D-glucan synthesis. Potent
fungicidal activity has been demonstrated against many Candida spp., including non-albicans
Candida spp. and fluconazole-resistant strains, as well as fungistatic activity against Aspergillus
spp. Owing to low oral bioavailability, it can only be administered intravenously. Anidulafungin
is not metabolized by the liver and renal clearance is negligible, thus rendering dosage
adjustments in patients with impaired hepatic or renal function unnecessary. Due to lack of
interference with the cytochrome P450 pathway, it displays minimal drugdrug interaction.
Anidulafungin has been approved by the US FDA for the treatment of esophageal and invasive
candidiasis after clinical trials demonstrated its noninferiority to fluconazole. In September
2007, anidulafungin gained EMEA approval for the treatment of invasive candidiasis in adult
non-neutropenic patients. For those with invasive or noninvasive candidiasis with resistance or
intolerance to fluconazole in particular, as well as those requiring antifungal medication, that
anidulafungin does not interact with concomitant medication means it may be regarded as a
safe and efficacious treatment option. Promising results from animal models and experience
with the other echinocandins indicate several potential lines of investigation: invasive
aspergillosis, prophylaxis and treatment of transplant patients, and empirical treatment in
patients with febrile neutropenia. Significant differences in clinical efficacy or safety favoring
anidulafungin over the other echinocandins are yet to be discovered.
KEYWORDS: anidulafungin antifungal agents aspergillosis candidiasis drug therapy echinocandins invasive
fungal infection therapeutic use

Over the last two decades, the incidence of

opportunistic fungal infections has been steadily increasing for a number of reasons: iatrogenic immunosuppression due to chemotherapy or systemic glucocorticosteroid therapy,
broad-spectrum antibiotic therapy, prevention
of transplant rejection after hematopoietic stem
cell or solid organ transplantation, use of
increasingly invasive medical procedures and
acquired immunosuppression after HIV infection [13]. In this context, Candida spp. and
Aspergillus spp. are well recognized as the two
most frequent fungal pathogens and are associated with high morbidity and mortality rates
[46]. While mortality from invasive aspergillosis
seems to be declining [7,8], the emergence of
azole-resistant non-albicans Candida spp., particularly Candida glabrata, has been observed
with great concern [9]. These recent developments, as well as polyene-associated nephrotoxicity [1012], have led to a growing interest in
alternative classes of antifungal agents, especially the echinocandins. They are characterized
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10.1586/17512433.1.2.207

by their common mode of action, the inhibition of -(1,3)-D-glucan synthesis, an essential

cell wall component of many pathogenic fungi.
Currently, three echinocandins are commercially available on the USA market: anidulafungin (Eraxis, Pfizer Inc., NY, USA), caspofungin (Cancidas, Merck & Co., Inc., NJ, USA)
and micafungin (Mycamine, Astellas Pharma
Ltd., IL, USA). Caspofungin was the first to
gain US FDA approval for use in the USA after
clinical trials demonstrated its efficacy in the
treatment of esophageal [1315] and invasive candidiasis [16,17], as salvage therapy against invasive aspergillosis [18] and as empirical therapy in
patients with febrile neutropenia [19]. The second agent to receive FDA approval was
micafungin, its application being the prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation [20]
and the treatment of esophageal candidiasis [21].
Anidulafungin received FDA approval for
esophageal candidiasis [22] and invasive candidiasis in non-neutropenic patients in 2006 [23]

2008 Future Drugs Ltd

ISSN 1751-2433

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Rping, Vehreschild, Farowski & Cornely

and, in September 2007, it gained EMEA approval for the

treatment of invasive candidiasis in adult non-neutropenic
patients. Anidulafungin is a promising representative of the
echinocandins and will therefore be the subject of this article.
Chemical structure

Anidulafungin (VER-002 or LY-303366) is a semisynthetic

lipopeptide, derived from echinocandin B0 and synthesized
from a fermentation product of Aspergillus nidulans. Its complete chemical designation is 1-[(4R,5R)-4,5-dihydroxy-N2[[4-(pentyloxy)[1,1:4,1-terphenyl]-4-yl]carbonyl]-L-ornithine] echinocandin B [24]. It is composed of an amphiphilic
hexapeptide and an N-linked alcoxytriphenyl side chain
(FIGURE 1) [24]. By modification of this side chain, which is typical of all echinocandins, a unique physicochemical profile can
be conferred to each drug [25]. Anidulafungin is a white-tooffwhite powder that is practically insoluble in water and
slightly soluble in ethanol. The chemical formula and relative
molecular weight are C 58H73 N7O17 and 1140.3 g/mol,
respectively [24].

In vitro activity

Numerous studies have shown that anidulafungin exhibits

good in vitro fungicidal activity against many Candida spp.,
including non-albicans Candida spp. and fluconazole-resistant
species [2932]. Cota et al. reported superior activity of anidulafungin in comparison with caspofungin against isolates of
Candida glabrata [33]. Decreased susceptibility to anidulafungin has been observed in the strains Candida parapsilosis,
Candida guilliermondii and Candida lusitaniae [29,3436], and
paradoxical growth of Candida albicans and Candida tropicalis
have been reported at a median concentration equaling
16-times the corresponding minimum invasive concentration
(MIC) for anidulafungin [37]. Fungistatic activity has been
demonstrated against Aspergillus spp. [30,3840] and in a limited
fashion against the cyst form of Pneumocystis jirovecii [41], as
well as against some rare moulds, such as Penicillium marneffei,
Mucor spp., Madurella mycetomatis, Phialophora verrucosa and
Acremonium spp. [4143]. Several reports describe progressive
echinocandin cross-resistances of C. albicans after prolonged
echinocandin exposure [27,28,44]. Like all echinocandins, anidulafungin exhibits no activity against Cryptococcus neoformans,
Fusarium spp. and most zygomycetes.

Method of action & basis of drug resistance

As with all echinocandins, anidulafungin acts by noncompetitive inhibition of the membrane bound -(1,3)-D-glucan synthase. This enzyme complex polymerizes UDP-glucose into
-(1,3)-D-glucan, a substantial cell wall component of Candida
spp. and other yeasts. The exact mechanisms leading to consecutive fungal cell death remain unknown. The -(1,3)-D-glucan
synthase consists of a regulatory and a catalytic subunit, the latter being coded for by two genes, FKS1 and FKS2, that are
translated into Fks1p and Fks2p [26]. Mutations in the FKS1
gene have been associated with drug resistance [27,28]. The
altered protein structure of the -(1,3)-D-glucan synthase seems
to impair interaction between the drug and its target enzyme.

H H

OH

HO

O
HO

NH

H3C

N
H

NH

N
H
N

H
O

H
OH
H

H
OH

Figure 1. Anidulafungin.

208

CH3

HO
H
HC
HO 3

HN

H
O

OH
OH

OH
H

Animal models

Given the paucity of clinical trials on anidulafungin, research

results from animal models may allow a certain amount of
insight and perspective until more clinical data become available.
Pharmacokinetics & pharmacodynamics

Pharmacokinetic measurements of anidulafungin in healthy

rabbits revealed a linear plasma curve that fitted with an open
three-compartment model. Pharmacokinetic parameters did
not differ significantly between multiple and single-dose
administration. Substantial penetration into tissue sites could
be observed following multiple dosing
(0.110 mg/kg daily). The highest concentrations were found in lung and liver
tissue (0.85 0.16 to 32.64 2.03 and
0.32 0.05 to 43.76 1.62 g/g, respecOC5H11
tively). At higher doses of 0.5 mg/kg or
more, measurable concentrations in brain
tissue were detected (0.24 0.02 to
3.90 0.25 g/g) [45].
Drugdrug interaction

In a murine model of pulmonary aspergillosis, DBA/2 mice were pretreated with

cortisone acetate at doses ranging from 12.5
to 50 mg/kg bodyweight daily, followed by
administration of anidulafungin. Mortality
was significantly elevated in the uninfected
yet cortisone-pretreated control group [46].

Expert Rev. Clin. Pharmacol. 1(2), (2008)

Anidulafungin

The investigators concluded that a deleterious drug interaction

had occurred between glucocorticoids and anidulafungin. However, this conclusion may be questioned by the lack of a control
group receiving glucocorticoids only. The unusually high dosage
of glucocorticoids in these experiments may very well have
caused the reported toxicity alone. Another study in rabbits has
failed to confirm this increase of toxicity during the concomitant
administration of glucocorticoids and anidulafungin [47].
Efficacy

Several animal studies investigated anidulafungin efficacy in the

treatment of invasive candidiasis. Using a murine model,
Petraitiene et al. compared the efficacy of anidulafungin in
invasive candidiasis by C. albicans with that of fluconazole and
amphotericin B [48]. At doses of 0.5 mg/kg or more daily, anidulafungin efficacy was equivalent to that of the other two drugs
tested, while serum creatinine concentrations were lower than
with amphotericin B [48].
Ostrosky-Zeichner et al. showed the superior efficacy of anidulafungin in immunosuppressed CF-1 mice, challenged by
intravenous injection of C. krusei, compared with that of fluconazole and amphotericin B (p 0.002 in all comparisons) [49].
Two studies used a C. glabrata-infected mouse model of
invasive non-albicans candidiasis. Gumbo et al. demonstrated
the persistence and continued antifungal action of anidulafungin in deep infected organs over a period of 96 h after drug
administration [50]. In the second study, comparing the activities of anidulafungin and caspofungin, the previously
observed superior in vitro activity of anidulafungin did not
translate into enhanced in vivo efficacy against C. glabrata. Both
drugs were similarly effective in reducing the fungal burden in
kidney tissue [51].
In a study examining oropharyngeal and esophageal candidiasis caused by fluconazole-resistant C. albicans in a rabbit model,
anidulafungin was superior to amphotericin B and fluconazole
in clearing the organism from all sites studied [52].
Anidulafungin efficacy has been tested in models of invasive
aspergillosis. Using a murine model, Verweij et al. compared
the therapeutic activities of anidulafungin and amphotericin B
in intravenously infected mice [53]. Anidulafungin proved to be
effective against amphotericin B-susceptible and -resistant
Aspergillus fumigatus isolates. Roberts et al. compared the
prophylaxis and treatment of invasive aspergillosis with ravuconazole and anidulafungin in immunocompromised rabbits [54].
While both drugs effectively reduced mortality and serum
galactomannan levels, anidulafungin failed to significantly
reduce the tissue burden of A. fumigatus. These findings are
consistent with the results of Petraitis et al.. In a rabbit model,
they assessed the prophylactic and therapeutic efficacy of anidulafungin in pulmonary aspergillosis. Significantly higher survival and less pulmonary injury were reported for both indications, and no toxic effects were observed. However, microscopic
examination revealed a dose-dependent progressive reduction
in length and increasing swelling of hyphal elements, while the

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Drug Profile

individual hyphal units remained viable [55]. Roberts et al.

recovered such microcolonies at the end of the experimental
phase and subjected them to further in vitro incubation,
whereupon they reverted to macrocolonies [54]. In a more
recent study, synergy of voriconazole and anidulafungin in the
treatment of pulmonary aspergillosis was observed in a rabbit
model [56].
Susceptibility of P. jiroveci to anidulafungin was studied in
a rat model suppressed by dexamethasone [41]. Efficacy was
assessed through transmission electron microscopy of lung
tissue. While cyst forms were practically eliminated from the
lungs after 4 days of treatment, the trophic forms merely displayed cytoarchitectural changes that were interpreted as the
result of interference with the transport of cell wall components. Whether this partially fungicidal activity will be of use
in a clinical setting remains subject to further investigation.
Pharmacodynamics, pharmacokinetics & metabolism
General aspects & parameters

As with all current echinocandins, anidulafungin is only available for intravenous administration. Plasma concentrations after
injection are dose proportional without significant intersubject
variability in general and special populations [57,58].
After administration of a loading dose equaling twice the daily
maintenance dose, steady state is achieved within 24 h [58], with
a short distribution half-life of 0.51 h. The volume of distribution at steady state (Vss) of 3050 l is similar to body fluid volume [57]. Anidulafungin is 99% protein bound and has a plasma
clearance of approximately 0.93 l/h. Terminal elimination
half-life averages 4050 h [47].
Hepatic metabolism of anidulafungin has not been observed,
thus limiting interactions with other drugs by concomitant use
of the cytochrome P450 pathway. Slow, nonenzymatic degradation processes facilitate the transition of the molecules structure from a closed to an open ring form. This intermediate substrate is further metabolized by unspecific plasma proteases and
excreted via bile, together with the 10% of the drug that is not
metabolized [59]. Digestion by salival enzymes has been
reported and might explain occasional breakthrough superficial
yeast infections [60].
A paradoxical increase of metabolism at high dosages, as has
already been demonstrated by caspofungin, was observed in
five out of 11 A. fumigatus, two out of eight Aspergillus terreus
and none out of eight Aspergillus flavus isolates using the CLSI
M38-A broth microdilution method. At 10.8 g/ml, 50% of
the maximal paradoxical increase of metabolism occurred [61].
Special populations

Anidulafungin does not require dosage adjustment in patients

with renal insufficiency and end-stage renal disease. It is not
dialyzable and may therefore be administered without regard
to the timing of hemodialysis [62]. While mild and moderate
hepatic impairment seem to have no impact on anidulafungin

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Rping, Vehreschild, Farowski & Cornely

pharmacokinetics, patients with severely impaired hepatic

function, that is, ChildPugh score 1015, displayed a
decrease in plasma concentration and area under the curve
(AUC) of 36 and 33%, respectively. Since plasma concentrations still remained well above the minimum inhibitory concentration of most clinically relevant fungal pathogens, and
since alterations in pharmacokinetics (C max, AUC, half-life
and Vss) and clearance remained within the range previously
reported for healthy subjects, these findings were considered
clinically negligible. The authors discuss that their findings
may have been related to an increased volume of distribution
due to ascites and edema [62].
A multicenter, open-label, ascending dosage study examined
the administration of two different dosages schemes (0.75 and
1.5 mg/kg once daily) in two cohorts of neutropenic pediatric
patients (211 years [n = 12] and 1217 years [n = 13]). These
dosages had been extrapolated from adult studies (50 and
100 mg once daily, respectively). Pharmacokinetic parameters
did not show significant differences between the two age
cohorts or any drug-related serious adverse events. The
recorded drug concentration profiles were similar to those
observed in adult usage [63]. For an observational study that was
launched in 2006, blood and urine samples of neonates are currently being collected to measure concentrations of antimicrobial products, including anidulafungin. Analysis of these data
may yield further information on the pharmacokinetics of this
special pediatric population [101].
Drugdrug interaction profile

Trials on drugdrug interaction have shown a favorable profile

for anidulafungin. The coadministration of anidulafungin and
tacrolimus in 35 healthy subjects neither caused significant
alterations in the pharmacokinetics of either drug, nor was
any additional toxicity reported [64]. The same conclusion was
drawn from studies in which anidulafungin was coadministered with voriconazole [65], amphotericin B [66], rifampin and
other metabolic substrates, inhibitors or inducers of cytochrome P450 [67]. Simultaneous administration of anidulafungin and ciclosporin A led to a 22% increase in the AUC of
anidulafungin. However, C max remained constant and the
interaction was therefore categorized as not clinically significant [67]. As yet, no significant interactions with efavirenz or
nevirapine have been reported.
Safety & tolerability

Thus far, several hundreds of patients have been included in

studies involving anidulafungin administration and the drug
has displayed an excellent safety profile. Most of the side
effects reported from several clinical trials, including a
Phase II study, were unspecific drug reactions, the most frequent being headache, fever, nausea, abdominal pain, vertigo
and injection-site reactions [63,65,68,69]. In some cases, slightly

210

increased liver function tests have been observed, which were

reversible upon discontinuation [67]. Infusion-related flushing
and temporary dyspnea have occurred occasionally. All
adverse events could be controlled by the use of diphenhydramine, reduction of the infusion rate or discontinuation of
the infusion [62,63,69]. These observations were confirmed in a
recent clinical trial reporting on 245 patients; no serious
adverse events related to anidulafungin occurred [23]. Anidulafungin does not seem to affect ECG parameters, especially
the QT interval.
Data on anidulafungin maximum cumulative dose are not
available but, in clinical studies, the administration of anidulafungin 100 mg once daily over 90 days caused no additional
adverse events [67]. In another study involving ten healthy subjects, a single loading dose of 260 mg followed by 130 mg once
daily was well tolerated. Three subjects experienced transient,
asymptomatic elevation of liver enzymes [58]. More extensive
studies on maximum dosage are not available at this time.
Regulatory affairs

Anidulafungin is available in the USA as Eraxis (Pfizer

Inc., NY, USA), where it has gained approval for the treatment of candidemia and other forms of Candida infections
(intra-abdominal abscess and peritonitis), as well as esophageal candidiasis. While Argentina and The Philippines have
already conferred their official approval, and the EMEA
approved anidulafungin for the treatment of invasive candidiasis in adult non-neutropenic patients in September 2007.
In the EU, however, the substance will be approved for the
treatment of invasive candidiasis in adult, non-neutropenic
patients only.
Clinical efficacy

When evaluating results from in vitro and animal studies, one

should remember that experimental success is not necessarily
representative of clinical performance. Host factors, such as
neutrophil and monocyte activity, have been shown to interact
with antifungal activity [70]. Also, the correlation between
in vitro MIC values and actual response to antifungal treatment
has not yet been prospectively investigated.
To date, clinical trials on anidulafungin have focused on the
treatment of invasive and noninvasive candidiasis (TABLE 1).
A multicenter, randomized, double-blind, double-dummy,
noninferiority trial compared the efficacy and safety of intravenous anidulafungin 50 mg once daily with that of oral fluconazole 100 mg once daily in the treatment of patients with
esophageal candidiasis (>95% C. albicans) [22]. From the 601
recruited patients, 504 were eligible for efficacy analysis. Concerning the rate of successful endoscopic response, the primary end point, anidulafungin was considered noninferior to
fluconazole (97.2 vs 98.8%, respectively). However, results
for anidulafungin were significantly worse when the sustained

Expert Rev. Clin. Pharmacol. 1(2), (2008)

Anidulafungin

Drug Profile

Table 1. Anidulafungin clinical trials.

Indication

Daily dosage

Patients eligible Efficacy end points

for evaluation (n)

Esophageal
candidiasis

Anidulafungin
504 (249
50 mg once daily
anidulafungin,
intravenously vs
255 fluconazole)
fluconazole 100 mg
once daily orally
(both double dose
on day one)

Primary: endoscopic
response at EOT
Secondary: clinical and
mycological response
at EOT

Primary: 97.2 vs 98.8%

Noninferiority of
sustained endoscopic
anidulafungin
response at 2 weeks FU
to fluconazole
64.4 vs 89.5%
Secondary: clinical success
98.8 vs 99.6%, mycological
success 86.7 vs 90.9%

[22]

Invasive
candidiasis

Anidulafungin 50,
75 or 100 mg once
daily intravenously
(double dose on
day one)

Primary: Global
response at FU
Secondary: Global
response at EOT

Primary: 72 (50 mg), 85

Trend towards
(75 mg) and 83% (100 mg) superiority of
Secondary: 84 (50 mg), 90 the higher dose
(75 mg) and 89% (100 mg)

[69]

Invasive
candidiasis

Anidulafungin
245 in MITT analysis Primary: global
100 mg once daily
response at end of
intravenously vs
intravenous treatment
fluconazole 400 mg
Secondary: global
once daily orally
response at end of all
(both double dose
study treatment and at
on day one)
2 and 6 weeks FU

Primary: 75.6 vs 60.2%

Secondary: end of all study
treatment 74 vs 56.8%,
FU 2 weeks 64.6 vs 49.2%,
FU 6 weeks 55.9 vs 44.1%

[23]

83 (25 with 50 mg,

30 with 75 mg,
28 with 100 mg) at
EOT, 68 at FU

Results

Conclusion

Noninferiority
and possibly
superiority of
anidulafungin
to fluconazole

Ref.

EOT: End of treatment; FU: Follow-up; MITT: Modified intention to treat.

response 2 weeks after treatment was evaluated (64.4 vs

89.5%; p < 0.001). The latter results are of special interest,
since an earlier randomized trial of caspofungin in esophageal
candidiasis had already registered a higher relapse rate with
caspofungin than with fluconazole at follow-up [14]. Most participants were HIV positive and more patients in the fluconazole arm than in the anidulafungin arm received antiretroviral
treatment during the trial period (58 vs 26 patients). This
may have confounded follow-up results.
In a Phase II open-label, dose-ranging study, 123 patients
with invasive candidiasis were randomized to one of three
treatment arms of 50, 75 or 100 mg once daily, preceded by a
loading dose twice the daily dose. The primary efficacy criterion was a successful global response rate in the evaluable
population at the follow-up visit, 2 weeks after the end of
therapy. In all three groups, treatment was safe and efficacious, with a trend towards superiority of the higher dose.
However, from the 123 patients enrolled, only 68 completed
the study. The majority of withdrawals were due to the
33 fatalities. Furthermore, investigators had not been blinded
and no standard-care comparator group was included, meaning that differences between the outcomes of each group
might have been distorted by factors such as catheter management or supportive care [69]. During the same study, baseline
isolates of Candida spp. were obtained and tested for susceptibility to anidulafungin and the four comparator antifungals
fluconazole, voriconazole, amphotericin B, and caspofungin.
The overall median anidulafungin MIC was 0.25 g/ml, with
C. parapsilosis (MIC50 and MIC 90 <1 g/ml) being the least
susceptible species. One strain of C. tropicalis displayed resistance to anidulafungin (MIC: 2 g/ml). Nevertheless, the
strain was eradicated during the course of the study [71]. The

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outcome of this trial is consistent with the results from a

Phase III randomized, double-blind, multicenter trial comparing anidulafungin (200 mg loading dose and 100 mg
once-daily maintenance) with fluconazole (800 mg loading
dose and 400 mg once-daily maintenance) for the treatment
of invasive candidiasis in a predominantly non-neutropenic
population (97%) [23]. Even though this trial was designed
primarily as a noninferiority trial, it included a two-step statistical analysis for superiority. Of a total of 261 patients
enrolled, 245 (anidulafungin [n = 127]; fluconazole
[n = 118]) were found eligible for efficacy analysis, which
yielded significantly higher response rates (75.6 vs 60.2%)
and better survival (74 vs 69%) for anidulafungin (p = 0.01).
However, superiority had to be recategorized to noninferiority
when the site with the highest enrollment numbers was
removed from the analysis. In conclusion, the results of this
study show noninferiority of anidulafungin compared with fluconazole. The small number of neutropenic patients, patients
with noncandidemic invasive candidiasis and the exclusion of
pediatric patients were regarded as further limiting factors of
this study.
Frequency and MIC of Candida spp. strains collected during the study did not deviate from those observed in earlier
studies [72,73]. Once again, C. parapsilosis proved to be the
species with the lowest susceptibility to anidulafungin.
Based on the results of the studies discussed in this review,
anidulafungin dosages for different indications have been
established (TABLE 2).
In a cost-effectiveness analysis of anidulafungin versus fluconazole in the treatment of confirmed invasive candidiasis, anidulafungin was shown to be the more economic alternative,
despite an increase in drug costs [74].

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Rping, Vehreschild, Farowski & Cornely

Table 2. Anidulafungin dosage for approved indications.

Indication

Daily dosage

Duration of treatment

Invasive candidiasis

200 mg first day loading dose,

100 mg daily maintenance dose

Based on clinical response, continuation for at least 14 days after

the last positive culture

[23,69]

Esophageal candidiasis

100 mg first day loading dose,

50 mg daily maintenance dose

A minimum of 14 days and at least 7 days following resolution of

symptoms, consider continuous treatment in HIV patients

[22]

According to ClinicalTrials.gov, a Phase IV nonrandomized,

open-label, uncontrolled trial with a scheduled enrolment of
300 patients should evaluate possible alternatives to the standard
anidulafungin treatment schedules for invasive candidiasis [101].
Treatment of invasive candidiasis should be continued for at
least 14 days after the last positive culture (TABLE 2). The limits
tested in this study will be either a shorter duration of 5 days or
a longer duration of up to 28 days. While the primary efficacy
end point will be the global response consisting of a combination of clinical and microbiological responses at the end of treatment, secondary outcome measures will include global response
rate at the end of intravenous treatment as well as the week 2
and 6 follow-up visits. Initiation of recruitment is planned for
the near future.

Expert commentary

Anidulafungin, a recently approved echinocandin, acts by

inhibition of -(1,3)-D-glucan synthesis. It has demonstrated
fungicidal activity against most Candida spp., including Candida non-albicans and fluconazole-resistant strains. In vitro
studies suggest reduced activity against C. parapsilosis, C. guilliermondii and C. lusitaniae, and clinical data on treatment of
these infections with anidulafungin are scarce. Cases of
C. albicans cross-resistance after treatment with caspofungin
have been reported. Anidulafungin exerts fungistatic activity
against Aspergillus spp., cyst forms of P. jiroveci and some other
rare moulds. Anidulafungin does not interact with the cytochrome P450 pathway, but is metabolized by slow nonenzymatic degradation. Renal clearance is virtually nonexistent.
These factors account for anidulafungins favorable drugdrug
interaction and tolerability profile, even in patients with
impaired hepatic or renal function. Promising results have
been reported from animal models of invasive aspergillosis. A
clinical trial has shown noninferiority of anidulafungin to fluconazole in the treatment of esophageal candidiasis, considering the significantly higher relapse rate after 2 weeks was probably confounded by differences in the treatment of underlying
disease. Anidulafungin is noninferior to fluconazole in the
treatment of invasive candidiasis and arguably also superior.

Five-year view

Anidulafungins favorable drugdrug interaction and tolerability profile markedly distinguishes this echinocandin from the
other classes of antifungal agents. In particular, its compatibility

212

Ref.

with immunosuppressive drugs, such as ciclosporin A and tacrolimus, hints at its potential as a drug for patients undergoing
allogeneic stem cell or solid organ transplantation. Further clinical studies in this setting, particularly regarding antifungal
prophylaxis, are warranted. Preterm neonates are another population that might profit from prophylactic treatment, although
this application remains controversial.
Considering that there seems to be little variation in the
characteristics of the different echinocandins, indications that
have already been approved for micafungin and caspofungin
should also be evaluated for anidulafungin, thus making
empirical antifungal treatment in febrile neutropenia and second-line treatment against invasive aspergillosis conceivable
future indications.
The role of echinocandin-class antifungals in treating P. jiroveci
pneumonia has yet to be defined.
Currently, anidulafungins restriction to intravenous administration remains its major limitation and excludes it as a firstline treatment option in uncomplicated fungal infections. Considering anidulafungins prolonged half-life, a switch to oral fluconazole after at least 34 days of treatment seems warranted,
provided that the patient is able to tolerate oral medication, has
been hemodynamically stable and afebrile for at least 24 h and
has recent blood cultures negative for Candida spp.
Ultimately, the future perspective of all three echinocandins
might depend on the crucial question: are there significant differences in clinical efficacy or safety favoring one echinocandin
over its competitors [75]?

Financial & competing interests disclosure

Potential conflicts of interest: F Farowski: no conflict. MJ Rping has

received grants from Schering-Plough/Essex and Gilead. JJ Vehreschild
has received grants from Gilead, Merck/MSD, Pfizer and ScheringPlough/Essex. OA Cornely has received research grants from Astellas,
Basilea, Gilead, Merck/MSD, Pfizer, Schering-Plough and Vicuron; is
a consultant to Astellas, Basilea, Gilead, Mlnlycke, Merck/MSD,
Nektar, Pfizer, Schering-Plough and Zeneus/Cephalon; and served on
the speakers bureau of Astellas, Gilead, Merck/MSD and ScheringPlough. OA Cornely is supported by the German Federal Ministry of
Research and Education (BMBF grant O1KNC706). The authors have
no other relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict
with the subject matter or materials discussed in the manuscript apart
from those disclosed.
No writing assistance was utilized in the production of this manuscript.

Expert Rev. Clin. Pharmacol. 1(2), (2008)

Anidulafungin

Drug Profile

Key issues
Chemical structure of anidulafungin:
Anidulafungin is a semi-synthetic lipopeptide, derived from echinocandin B0 with an N-linked alcoxytriphenyl side chain. It is insoluble
in water and slightly soluble in ethanol
Method of action & basis of drug resistance:
Anidulafungin acts via noncompetitive inhibition of the -(1,3)-D-glucan synthase.
FKS1 and FKS2 code for the catalytic subunit of the -(1,3)-D-glucan synthase; mutations in FKS1 are associated with drug resistance.
Animal models:
Clearly favorable results in invasive and esophageal candidiasis have been demonstrated and promising results for efficacy in
pulmonary aspergillosis, invasive aspergillosis and Pneumocystis jiroveci pneumonia have also been observed.
Pharmacodynamics, pharmacokinetics & metabolism:
Anidulafungin is only available as intravenous solution, owing to poor bioavailability and has a long half-life allowing once-daily
administration and linear pharmacokinetics over the therapeutic dose range. No dose adjustment is needed for patients with impaired
hepatic or renal function; however, loading dose equaling twice the daily maintenance dose is required.
Drugdrug interaction profile:
There is no interaction with cytochrome P450 pathway and anidulafungin and there are no significant interactions known; interaction
trials have been performed with ciclosporin A, tacrolimus, rifampin, amphotericin B and voriconazole.
Safety & tolerability:
Anidulafungi demonstrates good tolerability with occasional episodes of headache, fever, nausea, abdominal pain, vertigo and
injection-site reactions.
Slight elevation of liver enzymes has been observed.
No alteration of ECG parameters.
Regulatory affairs:
Anidulafungin gained EMEA approval for the treatment of invasive candidiasis in adult non-neutropenic patients in September 2007
and has official approval in the USA, Argentina and The Phillipines.
Clinical efficacy:
Anidulafungin has shown to be noninferior to fluconazole in the treatment of esophageal candidiasis; it is noninferior and arguably
superior to fluconazole in the treatment of invasive candidiasis.
Five-year view:
Possible future indications include antifungal prophylaxis and treatment in transplant patients, fever of unknown origin in neutropenic
patients and second-line treatment of invasive aspergillosis. Trials on clinical efficacy against Aspergillus spp. and perhaps P. jiroveci are
also warranted, as well as a definition of distinguishing characteristics among the echinocandins.
4

Lin SJ, Schranz J, Teutsch SM. Aspergillosis

case-fatality rate: systematic review of the
literature. Clin. Infect. Dis. 32(3), 358366
(2001).

Wenzel RP. Nosocomial candidemia: risk

factors and attributable mortality. Clin.
Infect. Dis. 20(6), 15311534 (1995).

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Website
101

ClinicalTrials.gov
www.clinicaltrials.gov

Affiliations

Maria J Rping
Uniklinik Kln, Klinik I fr Innere
Medizin, Klinisches Studienzentrum,
Schwerpunkt Infektiologie II, Bachemer
Str. 86, 50931 Kln, Germany

Jrg J Vehreschild
Uniklinik Kln, Klinik I fr Innere
Medizin, Klinisches Studienzentrum,
Schwerpunkt Infektiologie II, Bachemer
Str. 86, 50931 Kln, Germany

Fedja Farowski
Uniklinik Kln, Klinik I fr Innere
Medizin, Klinisches Studienzentrum,
Schwerpunkt Infektiologie II, Bachemer
Str. 86, 50931 Kln, Germany

Oliver A Cornely MD
Uniklinik Kln, Klinik I fr Innere
Medizin, Klinisches Studienzentrum,
Schwerpunkt Infektiologie II, Bachemer
Str. 86, 50931 Kln, Germany
Tel.: +49 221 478 6494
Fax: +49 221 478 3611
oliver.cornely@ctuc.de

Expert Rev. Clin. Pharmacol. 1(2), (2008)