Pharmacokinetics, antifungal activity and clinical efficacy of anidulafungin in the treatment of fungal infections

Abstract

Importance of the field:

Anidulafungin is one of three available intravenous echinocandins that plays an important role in the treatment of serious fungal infections. Currently, anidulafungin is approved for the treatment of esophageal candidiasis, candidemia and other invasive Candida infections including intra-abdominal abscesses and peritonitis.

Areas covered in this review:

This paper covers a comprehensive review of anidulafungin.

What the reader will gain:

The reader will be provided the most recent data available regarding the pharmacology, pharmacokinetics, in vitro activity and clinical utility of anidulafungin for the treatment of serious fungal infections.

Take home message:

Echinocandin antifungals, such as anidulafungin, are now considered first line for the treatment of candidemia and invasive candidiasis, particularly in critically ill patients or those who have previously received azole therapy. Anidulafungin has potent in vitro activity against Candida and Aspergillus species, predictable pharmacokinetics that does not require dosage adjustment, few drug interactions and is well tolerated. Because of these favorable characteristics, anidulafungin is an important addition to our antifungal armamentarium.

1. Introduction

Among pathogenic fungi, Candida species are the most common cause of invasive disease in humans, initiating a range of infections from mucocutaneous tissue disorders to invasive candidiasis and candidemia [1,2]. The treatment of invasive Candida infections has been challenged by underlying host factors including immunosuppression and intensive care unit admission, difficulty in identifying organisms to the species level and changes in epidemiology at many health centers towards more frequent infection with resistant Candida species [2]. The mainstay for the treatment of invasive Candida infections remains fluconazole for most clinicians. However, triazole-resistant species including Candida glabrata and Candida krusei, along with the emergence of azole-resistant Candida albicans, which previously were uniformly susceptible to fluconazole, have made treatment decisions more critical. The introduction of the echinocandins, the first novel antifungal class in well over a decade, provides a new option for the treatment of invasive Candida infections. In 2009, updated clinical practice guidelines from the Infectious Disease

Society of America favored echinocandins for patients with moderately severe to severe illness, as well as for those patients who previously had received a triazole antifungal [3].

The first echinocandin approved in the US was caspofungin in 2002, followed by micafungin in 2005 and anidulafungin in 2006 (Box 1). At the time of writing, the approval order of these agents appears to dictate market share in the US [4]. Herein, we review the available pharmacology, microbiology and clinical literature on anidulafungin (also known as ECB, LY303366, V-echinocandin, VEC, VER 002 and VER-02), with a focus on studies published in recent years.

Box 1. Drug summary.

Drug name	Anidulafungin
Phase	Launched
Launched indication	Esophageal candidiasis; candidemia and other invasive Candida infections including intra-abdominal abscesses and peritonitis
Pharmacology description	Cell wall synthesis inhibitor 1,3-β-Glucan synthase inhibitor
Route of administration	Parenteral, intravenous
Chemical structure
Pivotal trial(s)	Esophageal candidiasis: randomized, double-blind, double-dummy, multi-center; anidulafungin (100 mg on day 1 followed by 50 mg/day) vs fluconazole (200 mg orally on day 1 followed by 100 mg/day); EOT response: anidulafungin, 97.2% vs fluconazole, 98.8%; TOC response: anidulafungin, 64.4% vs fluconazole, 89.5% Candidemia/invasive candidiasis: randomized, double-blind, multi-center; anidulafungin (200 mg on day 1 followed by 100 mg/day) vs fluconazole (800 mg orally on day 1 followed by 400 mg/day); EOT response: anidulafungin, 75.6% vs fluconazole, 60.2%, p = 0.01

EOT: End of therapy; TOC: Test of cure.

2. Pharmacology

2.1. Biochemistry

Echinocandins are a well-known class of lipopeptide antifungals originally discovered in the 1970s. Earlier echinocandins such as cilofungin had potent activity against Candida species, but had solubility, pharmacokinetic and potential toxicity issues [5]. Anidulafungin, a semi-synthetic lipopeptide synthesized from a fermentation produce of Aspergillus nidulans, is 1-[(4R,5R)-4,5-Dihydroxy-N²-[[4ʹʹ-(pentyoxy)[1,1ʹ:4ʹ,1ʹʹ-terphenyl]-4-yl]carbonyl]-L-ornithine]echinocandin B and has a molecular mass of 1140.3 D [6].

The lipophilic N-acyl side chain, a terphenyl group in anidulafungin (see structure in drug summary box), is required to retain activity against Candida and Aspergillus species [7,8]. These lipophilic side chains predominantly differentiate the three echinocandins resulting in variations in solubility, microbiological potency and pharmacokinetic disposition. Micafungin contains a similarly large aromatic side chain consisting of a phenyl-isoxazol-phenyl group, while caspofungin contains a long aliphatic side chain [9]. In contrast to the other echinocandins, anidulafungin is sparingly soluble in water; thus, older formulations required reconstitution with a solution containing 20% (w:w) dehydrated alcohol in water as an organic solvent. A newer formulation of anidulafungin is now available in the US that does not require alcohol as a solubilizer [6]. This newer formulation contains the exact same ingredients and quantities as previous formulations; however, changes to immediate storage conditions pre- and post-reconstitution of the anidulafungin lyophile determine if water or alcohol is required. Polysorbate 80, an agent that forms micelles in water, is now solely responsible for dissolution; the micelles harbor anidulafungin while in solution. As a result, anidulafungin vials must be stored in the refrigerator before and after reconstitution and dilution to aid the polysorbate 80 in solubilizing the drug. Additionally, total daily infusion volumes have also been reduced so that the 200-mg loading dose and 100-mg maintenance dose are now diluted in 260 and 130 ml, respectively, and infused over a more reasonable 180 and 90 min. Infusion volume reductions further assist solubility by concentrating polysorbate 80.

2.2. Mechanism of action

Similar to other echinocandins, anidulafungin mediates its antifungal activity via binding to and noncompetitive inhibition of (1,3)-β-D glucan synthase, a fungal-specific enzyme responsible for the synthesis of 1,3- β-D glucan [8]. This polysaccharide is an essential carbohydrate component of the fungal cell wall. As a result, echinocandins have activity only against fungal species that require substantial amounts of β-glucan for a stable cell wall, including Candida species, Aspergillus species, and mycelial forms of Blastomyces dermatitidis and Histoplasma capsulatum [10–12]. Anidulafungin, however, lacks activity against Cryptococcus neoformans, Rhizopus, Fusarium, Scedosporium species and the yeast forms of the dimorphic fungi, presumably because these fungi contain little β-glucan or lack this carbohydrate entirely. Of importance, human cells do not contain (1,3)- β-D glucan synthase, thereby, minimizing the potential for direct human cell toxicity.

Differences in echinocandin antifungal effects are also apparent between Candida and Aspergillus species. Among Candida, echinocandins are bactericidal, causing lysis of the cell membrane [13]. In Aspergillus species, however, antifungal effects are a result of membrane disruption causing irregular hyphae growth in which branched tips can be observed laterally [14]. This difference also precludes estimation of the MIC for echinocandins against Aspergillus species. The minimum effective concentration (MEC) is thus reported as the lowest concentration required to produce the morphological change from filamentous growth to non-filamentous growth [15].

3. Pharmacokinetics

Studies of anidulafungin pharmacokinetics in healthy volunteers have demonstrated low and variable absorption after oral administration; thus, anidulafungin is only available in an intravenous formulation. In healthy volunteers, anidulafungin displayed linear, dose-proportional pharmacokinetics with a volume of distribution of 30 – 50 l and a t_1/2 of ~ 24 h [16]. The disposition of anidulafungin in patients enrolled in Phase II and III clinical trials further support these observations. Dowell et al. performed a population pharmacokinetic analysis of blood samples from 225 patients enrolled in 4 clinical trials: esophageal candidiasis, invasive candidiasis, invasive aspergillosis and refractory mucosal candidiasis [17]. Table 1 provides the base population model estimates as determined via the NONMEM program. Anidulafungin pharmacokinetics was well defined by a two-compartment model. The inter subject variability on anidulafungin clearance was estimated to be 34.9%, which could be further explained by the influence of patient weight, gender and which study the patient was enrolled in. Clearance was increased with increasing body weight, slightly increased in males and greater in patients enrolled in the invasive candidiasis study. The last suggests there may be minor physiologic differences among patients who are more acutely ill, which would explain anidulafungin clearance. However, these covariates taken together accounted for < 20% of the interpatient variability and thus are believed to be clinically insignificant.

Table 1.

Summary of anidulafungin pharmacokinetic parameter estimates from a population analysis of 225 patients during Phase II and III clinical trials.

Pharmacokinetic parameter	Mean	s.d.
t1/2 (h)	25.9	8.42
Cl (l/h)	0.946	0.33
V1 (l)	9.97	NR
Q (l/h)	24.2	NR
V2 (l)	23.2	NR

Adapted from [17].

NR: Not reported in reference; Q: Intercompartmental clearance; V₁: Volume of central compartment; V₂: Volume of peripheral compartment.

Unlike other echinocandins, anidulafungin does not undergo hepatic metabolism. Instead, the parent drug experiences slow, non-enzymatic, chemical degradation to an inactive open-ring metabolite [18]. Mass balance studies using [¹⁴C]-labeled anidulafungin in rats and humans suggest that anidulafungin and its primary degradant are eliminated in the feces, presumably via biliary excretion. In agreement with these observations, studies in 20 patients with varying degrees of hepatic impairment and 26 patients with renal impairment found no clinically significant differences in the pharmacokinetic profile of anidulafungin when compared with matched (based on age, gender and body weight) healthy subjects [19]. A statistically significant decrease in peak plasma concentration and AUC by 36 and 33%, respectively, was noted in subjects with Child-Pugh score 10 – 15 (i.e., severe) hepatic insufficiency; however, the values for all pharmacokinetic parameters in these subjects remained in the range previously reported in other healthy volunteer studies. These decreases are suspected to be due to increases in volume of distribution secondary to ascites and edema in this population, but are still not considered clinically significant to justify dosage adjustment. Among patients with varying degrees of renal function including those with end stage renal disease receiving hemodialysis, there was no correlation with anidulafungin clearance and creatinine clearance. Additionally, there are no measurable amounts of anidulafungin in the collected dialysate [20]. On the basis of these studies, anidulafungin does not require dosage adjustment by hepatic or renal function (including hemodialysis), gender or age. To our knowledge, however, the pharmacokinetics of anidulafungin has not been explored systematically in obese and morbidly obese patients.

Among the echinocandins, anidulafungin has the largest volume of distribution [9,21]. Protein binding was previously reported as 84% using ultrafiltration methods, but was > 99% during equilibrium dialysis studies. Thus, protein binding is similar to micafungin, but greater than caspofungin (96%) [21]. Based on the degree of protein binding, it is unexpected that anidulafungin would have the highest degree of tissue penetration among the echinocandins, as determined in murine studies [22]. Although lipophilic, the high protein binding of anidulafungin along with its large molecular mass precludes it from extensive penetration into the cerebrospinal fluid (CSF) [23]. Animal studies have reported undetectable CSF concentrations even when using doses significantly greater than used clinically. However, brain parenchymal concentrations were ~ 10 – 20% that of serum in a rabbit model [24]. A single case report of a patient receiving micafungin 100 mg/day for a C. glabrata esophageal-pleural fistula and mediastinitis reported brain tissue levels after craniotomy of 0.28 μg/ml (0.26 μg/g), while simultaneous plasma concentration was 1.58 μg/ml [25].

Tissue penetration studies in humans have not been well described. A pharmacokinetic study in 20 healthy adult subjects was conducted to determine the bronchopulmonary disposition of anidulafungin when administered concomitantly with intravenous voriconazole [26]. Penetration into the epithelial lining fluid, representing extracellular concentrations, was ~ 22% of total concentrations in plasma. In contrast, penetration into alveolar macrophages, representing intracellular concentrations and the first line of defense against invading fungi in the lung, was 1420% (i.e., 14-fold greater) compared with plasma AUC. Nonetheless, concentrations were above the MEC₉₀ for Aspergillus species in both extra and intra-cellular compartments for the entire dosing interval. Significant alveolar macrophage concentrations have also been noted for micafungin as well, thereby, suggesting preferential intracellular penetration for the echinocandin class. The clinical significance of this observation has yet to be determined.

The pharmacokinetics of anidulafungin has been described in children with neutropenia at a high risk for invasive fungal infections [27]. Blood samples were obtained following the first and fifth doses of anidulafungin 0.75 or 1.5 mg/kg/day of body weight. Children were divided into two cohorts based on age for evaluation (2 – 11 years (n = 12) and 12 – 17 years (n = 13)). Anidulafungin pharmacokinetics appeared to be dose proportional in both cohorts. The mean steady-state values for Cl, volume of distribution at steady-state (V_ss) and t_1/2 were 0.018 l/h/kg, 0.54 l/kg and 22.9 h, respectively, for the low dose versus 0.016 l/h/kg, 0.43 l/kg and 19.9 h for patients receiving 1.5 mg/kg/day. The interpatient variability in Cl and V_ss were influenced by body weight but not age. Based on AUC, 0.75 and 1.5 mg/kg/day corresponded with anidulafungin adult doses of 50 and 100 mg/day. Both dosages were well tolerated in children.

4. In vitro activity

4.1. Candida species

Since the publication of past echinocandin reviews, the Clinical Laboratory Standards Institute (CLSI) has set breakpoints for the echinocandins against Candida species [28]. A susceptibility breakpoint of ≤ 2 μg/ml takes into account analyses of mechanisms of resistance, MIC population distributions, parameters associated with success in pharmacodynamic models and results from clinical efficacy studies. However, there were few patients during clinical trials infected with organisms with MIC values > 2 μg/ml and thus a resistance breakpoint, as is provided for triazoles, polyenes and 5-FC, is not provided. Instead, these organisms are referred to as nonsusceptible. Based on this breakpoint, anidulafungin provides 99% susceptibility against all Candida species when combined from the SENTRY surveillance program (2006 – 2007) [29]. Recent meetings by CLSI, however, have called into the question the utility of this ‘one size fits all’ susceptibility breakpoint, and thus drug and species-specific breakpoints have been proposed (see discussion below). Detailed MIC and susceptibility data for different Candida species compared with other antifungals are provided in Table 2.

Table 2.

In vitro activity of anidulafungin in comparison with other antifungals against Candida species collected during the 2006 – 2007 SENTRY surveillance program.

Species drug	MIC range (μg/ml)	MIC50 (μg/ml)	MIC90 (μg/ml)	Interpretative category (%) S/I*/R‡
Candida albicans (n = 771)
Anidulafungin	0.002 – 1	0.015	0.06	100/--/0
Caspofungin	0.03 – 1	0.12	0.25	100/--/0
Amphotericin B	≤ 0.12 – 1	0.5	1	100/--/0
5-FC	≤ 0.5 - > 64	≤ 0.5	1	97.9/0.1/2
Fluconazole	≤ 0.5 – 16	≤ 0.5	≤ 0.5	99.7/0.3/0
Voriconazole	≤ 0.06 – 0.25	≤ 0.06	≤ 0.06	100/0/0
Candida parapsilosis (n = 238)
Anidulafungin	0.03 – 4	2	2	95.4/--/4.6
Caspofungin	0.06 – 4	0.5	1	99.6/--/0.4
Amphotericin B	0.25 – 1	1	1	99.6/--/0.4
5-FC	≤ 0.5 - > 64	≤ 0.5	≤ 0.5	98.7/0/1.3
Fluconazole	≤ 0.5 – 32	1	4	96.6/3.4/0
Voriconazole	≤ 0.06 – 2	≤ 0.06	0.12	99.6/0.4/0
Candida glabrata (n = 202)
Anidulafungin	0.015 – 1	0.015	0.12	100/--/0
Caspofungin	0.06 – 2	0.25	0.25	100/--/0
Amphotericin B	≤ 0.12 – 1	1	1	100/--/0
5-FC	≤ 0.5	≤ 0.5	≤ 0.5	100/0/0
Fluconazole	≤ 0.5 - > 64	8	64	74.3/15.3/10.4
Voriconazole	≤ 0.06 – 8	0.25	1	90.1/3.5/6.4
Candida tropicalis (n = 157)
Anidulafungin	0.008 – 0.5	0.03	0.06	100/--/0
Caspofungin	0.06 – 2	0.12	0.5	100/--/0
Amphotericin B	≤ 0.12 – 2	1	1	98.1/--/1.9
5-FC	≤ 0.5 - > 64	≤ 0.5	≤ 0.5	94.9/0.6/4.5
Fluconazole	≤ 0.5 – 32	≤ 0.5	1	99.4/0.6/0
Voriconazole	≤ 0.06 – 0.5	≤ 0.06	≤ 0.06	98.1/0.6/1.3
Candida krusei (n = 29)
Anidulafungin	0.03 – 2	0.06	0.5	100/--/0
Caspofungin	0.25 – 4	0.5	1	96.6/--/3.4
Amphotericin B	0.25 – 2	1	1	93.1/--/6.9
5-FC	4 – 32	16	16	3.4/93.2/3.4
Fluconazole	8 - > 64	32	64	3.5/79.3/17.2
Voriconazole	0.12 – 2	0.25	1	93.1/6.9/0
Candida lusitaniae (n = 14)
Anidulafungin	0.12 – 0.5	0.25	0.5	100/--/0
Caspofungin	0.25 – 1	0.5	0.5	100/--/0
Amphotericin B	≤ 0.12 – 0.5	0.5	0.5	100/--/0
5-FC	≤ 0.5	≤ 0.5	≤ 0.5	100/0/0
Fluconazole	≤ 0.5 – 32	≤ 0.5	1	92.9/7.1/0
Voriconazole	≤ 0.06 – 0.25	≤ 0.06	≤ 0.06	100/0/0

Modified from [29].

^*Intermediate applies to 5-FC only. Triazole (fluconazole and voriconazole) intermediate is interpreted and reported as SDD. A dash indicates no intermediate or SDD category for the drug.

^‡There is no resistant breakpoint for echinocandins. Isolates with MIC values > 2 μg/ml are currently classified as nonsusceptible; however, CLSI has recently proposed changes to susceptibility breakpoints (see text).

5-FC: 5-Fluorocytosine; CLSI: Clinical Laboratory Standards Institute; I: Intermediate; MIC₅₀: Minimum inhibitory concentration that inhibits 50% of the isolates; MIC₉₀: MIC that inhibits 90% of isolates; R: Resistant; S: Susceptible; SDD: Susceptible-dose-dependent.

In general, anidulafungin portrays MIC values similar to micafungin against Candida species, both of which are four to eightfold more potent that caspofungin. Like other echinocandins, anidulafungin is less active against Candida parapsilosis with both MIC₅₀ and MIC₉₀ of 2 μg/ml and 95.4% of isolates defined as susceptible based on the current breakpoint of 2 μg/ml [26]. The reduced activity against C. parapsilosis is presumably due to a naturally occurring polymorphism of the gene responsible for glucan synthase [30]. As reported sporadically, however, anidulafungin appears to remain active against some C. parapsilosis isolates that have high MIC values to caspofungin and micafungin [31], and that lower concentrations of anidulafungin were required to induce cellular damage and distortion of the cellular morphology [32]. However, in vitro and in vivo studies using serum in varying concentrations with broth have demonstrated that anidulafungin MIC values increase to a greater extent than caspofungin against Candida species [33–35]. Thus, the higher protein binding observed for anidulafungin probably attenuates superior in vitro activity. Murine disseminated candidiasis models have thus concluded that in vivo efficacy is similar among the agents [30,36].

Resistance to the echinocandins among Candida species is conferred via mutations of the FKS1 or FKS2 subunits of glucan synthase, which cause amino-acid substitutions and prevent echinocandins from binding to and inhibiting the enzyme [37,38]. Fortunately, these mutations are rare and have not been noted in longitudinal surveillance studies to be decreasing in echinocandin potency [39]. Recent studies among various Candida species have challenged the accuracy of the current susceptibility breakpoint (i.e., ≤ 2 μg/ml) because a significant percentage of studied isolates harboring FKS gene mutations may have echinocandin MIC values in the susceptible range [40,41]. This was particularly true for anidulafungin and micafungin as their MIC values to wild-type Candida species are several dilutions below the susceptibility breakpoint. Applying this breakpoint with CLSI testing methodology, 89.2, 92.9 and 60.7% of FKS hot spot mutants were classified as susceptible to anidulafungin, micafungin and caspofungin, respectively [42]. Lowering the breakpoint based on epidemiological cutoff values, the MIC that contains 95% of isolates in the wild-type distribution, provided acceptable categorical agreement between different MIC tests for most echinocandin-Candida species comparisons [42,43]. As a result of these new analyses and integration of molecular, clinical and pharmacodynamic data, drug- and species-specific interpretative criteria have been proposed by CLSI. Clinical breakpoints of ≤ 0.25 μg/ml (susceptible), 0.5 μg/ml (intermediate) and ≥ 1 μg/ml (resistant) for all three echinocandins against C. albicans, Candida tropicalis and C. krusei are proposed. The data support the same breakpoints for anidulafungin and caspofungin against C. glabrata, but lower breakpoints for micafungin against this species: ≤ 0.06 μg/ml (susceptible), 0.25 μg/ml (intermediate) and ≥ 0.5 μg/ml (resistant). Finally, ≤ 2 μg/ml (susceptible), 4 μg/ml (intermediate) and ≥ 8 μg/ml (resistant) would categorize all echinocandins against C. parapsilosis [44].

Additionally, several in vitro and animal studies describe paradoxical growth of some Candida isolates at high, but not low, concentrations of echinocandins, termed the ‘Eagle Effect’. Proposed hypotheses for this phenomenon include upregulation of chitin in the cell wall, changes in cell-wall integrity and the contribution of calcineurin pathways [45,46].

4.2. Aspergillus species

Unlike Candida species, there are no interpretative susceptibility breakpoints for echinocandins against Aspergillus species. Nonetheless, echinocandins have potent in vitro activity against these moulds. Pfaller et al. recently reported the in vitro activity, as defined by the MEC, of anidulafungin, caspofungin and micafungin against 526 Aspergillus clinical isolates (A. fumigatus (n = 391), A. flavus (n = 64), A. niger (n = 46) and A. terreus (n = 25)) collected worldwide between 2001 and 2007 [47]. For anidulafungin and micafungin, the MEC₅₀ and MEC₉₀ against all isolates were 0.007 and 0.015 μg/ml, respectively, while values were typically higher for caspofungin (0.015 and 0.03 μg/ml, respectively). All but four isolates had MEC values ≤ 0.06 μg/ml for all three echinocandins. Similar potency of anidulafungin and the other echinocandins has been documented in other in vitro studies [26,48–50].

Because echinocandins are not fungicidal against Aspergillus species, they are often administered concomitantly with another mould active agent, such as amphotericin B, itraconazole, voriconazole or posaconazole. The in vitro activity of combinations of anidulafungin with these other agents has been evaluated in several studies against Aspergillus species. Philip et al. used in vitro checkerboard methodology to calculate the fractional inhibitory concentration index (FICI) of anidulafungin in combination with amphotericin B, itraconazole and voriconazole against 26 Aspergillus clinical isolates (A. fumigatus (n = 8), A. flavus (n = 8), A. niger (n = 5), A. terreus (n = 5)) [51]. An FICI ≤ 0.5 would be defined as synergy, 0.5 – 4 is indifferent and an FICI > 4 is antagonistic. The combinations of anidulafungin with either itraconazole or voriconazole resulted in synergy in 18 of 26 isolates with only 1 isolate of A. niger demonstrating antagonism to anidulafungin plus itraconazole. Synergy was predominantly seen among A. fumigatus and A. flavus species. In contrast, the combination of anidulafungin with amphotericin B resulted in mostly indifference (16 of 26 isolates), but antagonism was also noted in 5 of 26 isolates. In a separate study using slightly different methodology, but the same FICI classifications, anidulafungin plus voriconazole demonstrated mostly indifference against 31 Aspergillus species [52].

4.3. Other fungi

In addition to the above noted fungi, the echinocandins also demonstrate excellent activity against Pneumocystis jerovici, and this was originally in part why these agents were developed [53]. Although echinocandins have poor in vitro activity against the agents of mucormycosis, it is now known that Rhizopus oryzae expresses the echinocandin target on (1,3)-β-D glucan synthase [54]. In vivo animal infections models with all three echinocandins have demonstrated poor effects with monotherapy; however, survival benefits and synergistic reductions in kidney fungal burden were demonstrated when combined with liposomal amphotericin B [54–56]. Specific to anidulafungin, a synergistic benefit was noted in only a 10 mg/kg/day dose in mice, but not the 1 mg/kg/day dose [56]. Conversely, synergistic benefits with the other two echinocandins were only noted at lower doses. Clearly, further work in this area to explain the mechanism of synergy and determine the optimal dose of each echinocandin will be critical for use against these difficult to treat moulds.

5. Pharmacodynamics

The in vitro-in vivo pharmacodynamic activity of anidulafungin has been reviewed in previous publications [9,21,57]. Echinocandins exhibit concentration-dependent killing with a prolonged post-antifungal effect against Candida species. Animal infections models of invasive candidiasis as well as aspergillosis indicate that activity appears to be optimized when C_max:MIC/MEC ratios approach 10 or the tissue 24 h AUC:MIC ratio exceeds 250 [58–60]. Andes et al. recently characterized the pharmacodynamics of anidulafungin in a neutropenic murine candidiasis model to determine the most important pharmacodynamic indices (C_max/MIC, AUC/MIC or time that concentrations remain above the MIC) and quantitate the level of exposure needed for fungistatic effects as well as 1-log reductions in fungal burden [61]. The strongest relationship with antifungal effect was observed with the C_max:MIC and AUC:MIC ratios; furthermore, these observations were consistent across Candida species. The investigators used corrections for protein binding based on two different approaches, thus, resulting in free C_max:MIC ratios of 0.70 ± 0.72 and 14.1 ± 14.5 for 1-log reductions in fungal burden, depending on whether 99 or 84%, respectively, was used to correct for protein binding. Using the same protein binding assumptions, the free AUC:MIC ratio to produce the same effect was 13 ± 11.7 and 259 ± 231, respectively. A follow-up study by the same group compared all three echinocandins against C. albicans, C. glabrata and C. parapsilosis [36] and found that the free AUC:MIC ratio to achieve a 1-log reduction was similar for all three echinocandins, but varied by Candida species. Higher AUC/MIC exposures were required to get the same effect for C. parapsilosis compared with the other two species.

Most animal pharmacodynamic studies have demonstrated minimal effects when anidulafungin monotherapy was evaluated against Aspergillus species [62–65]. As echinocandins are likely to be administered in combination with voriconazole or amphotericin B, the pharmacodynamics and in vivo synergy of combination therapy with anidulafungin have been assessed in murine aspergillosis models [66–68]. Petraitis et al. evaluated the use of combination anidulafungin and voriconazole in persistently neutropenic rabbits with invasive pulmonary aspergillosis [67]. Rabbits inoculated with A. fumigatus received anidulafungin 5 mg/kg/day, 10 mg/kg/day, voriconazole 10 mg/kg q8h, a combination of the anidulafungin regimens plus voriconazole or no drug. In addition to assessing common outcomes variables such as survival, pulmonary infarct score, lung weight, residual fungal burden, pulmonary infiltrate volume, serum galactomannan index and bronchoalveolar lavage fluid galactomannan level, the investigators applied Bliss independence pharmacodynamic modeling to correlate in vitro and in vivo drug combinations as synergistic, independent or antagonistic. While in vitro synergy was noted for the combination, in vivo synergistic responses were only observed when voriconazole was combined with the lower anidulafungin dose. At the higher dosage, independence (i.e., no interaction) or antagonism was observed, depending on the outcome variable evaluated. Other animal pharmacodynamic studies have generally concluded that there is no benefit to adding anidulafungin to already active drugs such as amphotericin B and voriconazole [66,68]. The disparity noted among these studies is probably due to species-to-species differences, varying infection models and the delicate effect of the echinocandin dose on the observed outcome.

6. Clinical studies

6.1. Invasive candidiasis and candidemia

The first results reported for anidulafungin in invasive Candida infection were from Krause et al. in 2004 [69]. A Phase II, randomized, dose-ranging study was conducted to evaluate the safety and efficacy of anidulafungin in invasive candidiasis, including candidemia, to identify the optimal dose. One hundred and twenty-three patients were randomized to one of three intravenous regimens: 50, 75 or 100 mg once daily. The primary efficacy criterion was a successful global response rate (i.e., clinical and microbiological success) at the follow-up visit, which was scheduled for 2 weeks after the end of therapy. Success rates at the end of therapy were 84, 90 and 89% in the 50, 75 and 100 mg dose groups, respectively, for the 68 evaluable patients. Importantly, 94% of these patients had candidemia only. Eradication rates appeared to be dose-dependent: 74, 85 and 89% for the 50, 75 and 100 mg groups, respectively. As a result, the 100 mg dose was carried into randomized, controlled Phase III studies to confirm these results for the treatment of invasive candidiasis, including candidemia.

Using the results from the open-label, non-comparative, dose-ranging study [69], Pfaller et al. attempted to link Candida susceptibly with eradication rates among different species and dosage regimens [70]. The study results indicated a lack of in vitro-in vivo correlation which was largely due to the small number of isolates tested. Blood was cultured at baseline, during treatment, at follow-up visit and as clinically indicated. Ninety-four percent of patients had candidemia and only ten percent had Candida identified at another normally sterile site. All baseline isolates of Candida spp. (n = 127) from patients who received anidulafungin were tested against anidulafungin, fluconazole, voriconazole, amphotericin B and caspofungin. The overall median anidulafungin MIC was 0.25 μg/ml. Eradication rates of Candida spp. in 68 evaluable patients showed a dose-related trend among all 3 treatment groups, in which 61 of 73 baseline pathogens were eradicated, and the majority of these (n = 49) were documented by negative blood cultures.

In 2007, Reboli et al. compared anidulafungin with fluconazole in a randomized, double-blind, non-inferiority trial for the treatment of invasive candidiasis [71]. The primary efficacy criterion assessed was again the global response (i.e., clinical and microbiologic success) at the end of the intravenous therapy. Clinical success was defined as the resolution of signs and symptoms of invasive candidiasis and no requirement for additional systemic antifungal therapy. Microbiologic success was defined as the eradication of Candida species present at baseline, as determine by follow-up cultures, or the presumed eradication. Patients were randomly assigned to receive either intravenous anidulafungin (200 mg on day 1 followed by 100 mg/day thereafter) or intravenous fluconazole (800 mg on day 1 followed by 400 mg/day thereafter). After 10 days of intravenous therapy, all patients could be switched to oral fluconazole (400 mg/day). Patients received treatment for 14 – 42 days and for at least 14 days after a negative blood culture for improvement in signs and symptoms. Success rates at the end of the intravenous therapy were 60.2% in patients treated with fluconazole compared with 75.6% in patients treated with anidulafungin, which resulted in a 95% CI of the difference between the two treatments of 3.9 – 27%, p = 0.01. Differences remained significant during a multivariate logistic regression model that attempted to adjust for baseline characteristics of immunosuppressive therapy, diabetes mellitus, previous azole therapy, Candida species and catheter removal. Microbiologic success was observed for 88.1% of all baseline pathogens in the anidulafungin group compared with 76.2% of pathogens in the fluconazole group (p = 0.02). Removal of a single site that enrolled 10% of the modified intention-to-treat population resulted in 73.2 and 61.1% clinical success among anidulafungin and fluconazole, respectively; however, the difference was no longer statistically significant due to loss of power. Investigators concluded that anidulafungin was non-inferior to fluconazole in the treatment of invasive candidiasis.

6.2. Esophageal candidiasis

Anidulafungin has been less extensively studied in patients with esophageal candidiasis compared with caspofungin and micafungin. In 2004, Krause et al. published a randomized, double-blind, double-dummy study comparing safety and efficacy of anidulafungin (100 mg on day 1 followed by 50 mg/day thereafter) with fluconazole (200 mg orally on day 1 followed by 100 mg/day thereafter) [72]. Patients received treatment for 7 days beyond the resolution of symptoms (range, 14 – 21 days) for endoscopically and microbiologically documented esophageal candidiasis. Endoscopically-confirmed success rates were 98.8 and 97.2% for fluconazole and anidulafungin, respectively. Anidulafungin was found to be statistically non-inferior to fluconazole. A 2-week follow-up revealed that 89.5 and 64.4% of patients taking fluconazole and anidulafungin, respectively, had sustained success. Although, it is important to note that more patients in the fluconazole group were taking antiretrovirals concurrently. Investigators concluded that anidulafungin is as safe and effective as oral fluconazole for the treatment of esophageal candidiasis when assessed at the completion of therapy.

In 2008, Vazquez et al. published a Phase II, open-label, non-comparative study of the safety and efficacy of anidulafungin (100 mg on day 1 followed by 50 mg/day thereafter for 14 days or a maximum of 21 days) for azole-refractory oropharyngeal and esophageal candidiasis, which is frequently observed in patients who are immunosuppressed as a result of HIV, malignancy, post-transplant immunosuppressive therapy, persistent neutropenia, steroid use or diabetes [73]. Primary efficacy variables were clinical response for oropharyngeal candidiasis and both endoscopic and clinical responses for esophageal candidiasis at the end of therapy. Nineteen patients were enrolled in the study within 1 month of receiving a 14-day course of either fluconazole (> 200 mg/day) or voriconazole; clinical success was observed in 95% of patients and endoscopic success was observed in 92% of patients with esophageal candidiasis. At follow-up, clinical success was maintained in 47% of patients. Investigators concluded that anidulafungin was well tolerated and efficacious in the treatment of patients with azole-refractory esophageal and oropharyngeal candidiasis.

6.3. Invasive aspergillosis

Walsh et al. conducted an open-label, non-comparative, multi-center, pilot study evaluating the efficacy and safety of combination therapy with anidulafungin (200 mg on day 1 followed by 100 mg/day thereafter) and liposomal amphotericin B (up to 5 mg/kg/day) for the treatment of proven extrapulmonary or proven/probable pulmonary invasive aspergillosis [74]. The primary outcome was a global response (clinical and radiological) at the end of therapy in the modified-intention-to-treat analysis. Thirty patients received at least > 1 dose of anidulafungin, and 25 patients were included in the modified intention-to-treat analysis. The majority of patients in the study had probable pulmonary invasive aspergillosis while sites of extrapulmonary aspergillosis included CNS, liver, heart, bone, sinus, skin and prostate. The median duration of combination therapy was 22 days. The global response in the modified intention-to-treat analysis was 28% at the end of therapy and 20% at the follow-up assessment. Clinical and radiological success was observed at the end of therapy in 44 and 28% of patients, respectively, and 24 and 20%, respectively, at follow-up.

In 2008, a Phase IV, open-label pilot study was initiated in order to evaluate the combination of voriconazole and anidulafungin for the treatment of proven or probably invasive aspergillosis in patients who are intolerant to polyene treatment [75]. Six patients were enrolled in the study but unfortunately it was terminated due to slow rate of enrollment. Currently, a Phase III, prospective, randomized trial comparing efficacy and safety of anidulafungin and voriconazole in combination with voriconazole alone for the treatment of proven or probable invasive aspergillosis is ongoing [76].

7. Safety and drug interactions

Anidulafungin is generally well tolerated. A low rate of adverse drug events was observed in a review of Phase II and III clinical studies of patients with candidiasis, candidemia or aspergillosis who received anidulafungin doses of 50 – 100 mg/day, with loading doses of 100 or 200 mg, respectively [77]. In the randomized, double-blind, non-inferiority study comparing anidulafungin with fluconazole for the treatment of invasive candidiasis, the number of treatment-related adverse drug events was similar between the two groups, 24.4 and 26.4% for anidulafungin and fluconazole, respectively [71]. Elevated levels of hepatic enzymes were seen more frequently in the fluconazole group compared with the anidulafungin group. A Phase II, randomized, dose-ranging study evaluating safety and efficacy of anidulafungin in invasive candidiasis and candidemia found that events considered to be related to treatment were reported by 5% of patients in each dose group (50, 75 and 100 mg/day) with the exception of hypokalemia occurring in 10% of patients in the 50 mg/day dosage group [69]. The most common events were hypotension, vomiting, constipation, nausea and pyrexia. No dose-response relationship was observed with any of these adverse drug events. Forty-six percent of patients experienced at least one serious adverse event, but only three serious adverse events (i.e., nonfatal, non-neutropenic fever and two episodes of seizure) were reported as probably or possibly related to the treatment. Greater than 1700 doses of anidulafungin were administered and no systemic infusion-related adverse events occurred. A Phase II, open-label study of the safety and efficacy of anidulafungin as treatment for azole-refractory mucosal candidiasis observed that anidulafungin was well tolerated [72]. The most common adverse event noted was nausea and/or vomiting in 21% of patients. The most common treatment-related adverse event was hypokalemia reported by 11% of patients. There was one event reported by a patient experiencing a diffuse maculopapular rash, which resulted in discontinuation of anidulafungin and resolution of the rash. In a Phase III study comparing anidulafungin and fluconazole for the treatment of esophageal candidiasis, the most common adverse events were increases in γ-glutamyl transferase in 1.3% of patients in the treatment group, increases in aspartate aminotransferase in 0.3 versus 2.3% in anidulafungin and fluconazole, respectively, although the two study arms did not observe alteration in liver function tests. Possible histamine-mediated symptoms, including rash, urticaria, flushing, pruritis, dyspnea and hypotension, have been reported with anidulafungin. These events are infrequent when the rate of anidulafungin infusion does not exceed 1.1 mg/min.

In vitro and in vivo studies demonstrate that there are no clinically relevant drug-drug interactions observed with drugs likely to be co-administered with anidulafungin (Table 3) [6,18,78–80]. Anidulafungin is not a substrate for CYP and does not significantly inhibit CYP isoforms (1A2, 2B6, 2C8, 2C19, 2D6 and 3A).

Table 3.

Summary of studies defining clinically relevant drug interactions observed with drugs likely to be co-administered with anidulafungin.

Drug tested with anidulafungin	Findings
Cyclosporine (CYP3A4 substrate) 1.25 mg/kg p.o. twice daily on days 5 – 8 [78]	12 healthy adults received anidulafungin (200 mg on day 1 followed by 100 mg/day thereafter) in combination with cyclosporine. Steady-state AUC of anidulafungin was increased by 22%. Cyclosporine pharmacokinetics was not assessed. A separate in vitro study showed anidulafungin has no effect on the metabolism of cyclosporine [18]
Voriconazole (CYP2C19, CYP2C9, CYP3A4 inhibitor and substrate) 400 mg p.o. twice daily for day 1 followed by 200 mg p.o. twice daily [79]	17 healthy subjects received anidulafungin (200 mg on day 1 followed by 100 mg/day thereafter) in combination with voriconazole. The steady-state Cmax and AUC of anidulafungin and voriconazole were not significantly altered
Tacrolimus (CYP3A4 substrate) 5 mg p.o. single dose on day 1 [80]	35 healthy subjects received a single dose of tacrolimus in combination with anidulafungin (200 mg on day 1 followed by 100 mg/day thereafter on days 4 – 12 and in both combinations on day 13). The steady-state Cmax and AUC of anidulafungin and tacrolimus were not significantly altered
Liposomal amphotericin B (Ambisome®, Astellas, Parkway North Deerfield, IL, USA) [6]	Pharmacokinetics of anidulafungin was evaluated in 27 patients co-administered with liposomal amphotericin B. The pharmacokinetics of anidulafungin was comparable with data of patients from other studies who did not receive amphotericin B suggesting that the pharmacokinetics of anidulafungin was not significantly altered
Rifampin (potent CYP450 inducer) [6]	The pharmacokinetics of anidulafungin was evaluated in 27 patients co-administered with rifampin. The pharmacokinetics of anidulafungin was comparable with data of patients from other studies who did not receive rifampin suggesting that the pharmacokinetics of anidulafungin was not significantly altered

p.o.: By mouth.

8. Dosing and formulations

Anidulafungin sterile water for injection is supplied in single-use vials of sterile, lyophilized, preservative-free powder as 50 and 100 mg strengths, which can be used to prepare the required doses [6]. For the treatment of candidemia and other Candida infections, anidulafungin is administered as a single 200 mg loading dose infused over 180 min on day 1, followed by 100 mg infused over 90 min daily thereafter. For the treatment of esophageal candidiasis, all doses are reduced by a half (i.e., 100 mg load, followed by 50 mg/day). Anidulafungin must be stored in the refrigerator before reconstitution and after dilution to keep the product in solution. After dilution, stability in the refrigerator has been demonstrated for up to 24 h.

9. Conclusions

As a class, the echinocandins are an exciting and welcomed addition to the antifungal armamentarium. Anidulafungin is the latest addition among these agents and appears to be safe, well-tolerated and efficacious for the treatment of invasive and esophageal candidiasis. It may also have a role in the treatment of invasive aspergillosis when administered in combination with another mould-active antifungal. Anidulafungin’s unique pharmacokinetics and lack of drug interactions may make it particularly useful for patients receiving immunosuppressive medications which have a narrow therapeutic index and may interact with other available antifungals.

10. Expert opinion

The Infectious Diseases Society of America now recommends an echinocandin antifungal as first line for the treatment of candidemia and invasive candidiasis, particularly in critically ill patients or those who have previously received azole therapy. Anidulafungin is one of three available intravenous echinocandins that plays an important role in the treatment of serious fungal infections. Although certain pharmacologic characteristics differentiate the echinocandins, current data suggest that all the three should provide similar effectiveness for the treatment of Candida infections.

Anidulafungin displays a very predictable pharmacokinetic profile that is both linear and dose-proportional. Unique to anidulafungin is its natural degradation to inactive metabolites; thus, its half-life is ~ 24 h (longer than the other agents) in both healthy volunteers as well as severely ill patients and no dosage adjustments are required for renal or hepatic impairment. The long half-life also supports administration of a loading dose to obtain steady-state concentrations after the second or third dose. Like other echinocandins, anidulafungin is highly protein bound (> 99%), but has the largest volume of distribution of the class, thereby resulting in very high tissue and intracellular concentrations, a characteristic typically not observed among other highly protein bound drugs. Nonetheless, the clinical significance of its high penetration and tissue concentrations has yet to be understood. Murine models of invasive candidiasis suggest that the overall free drug exposure as defined by the fAUC/MIC is most predictive of antifungal killing for the echinocandins, and after controlling for protein binding, the pharmacodynamic targets predictive of static- and cidal-responses are actually very similar for all three agents. This suggests that any increase in microbiological potency afforded to anidulafungin and micafungin over caspofungin against Candida species is probably offset by the lower protein binding with the latter.

Previous formulations of anidulafungin were hampered by the compound’s insolubility, thus requiring alcohol, large volumes, and slow infusion times to keep it in solution and prevent infusion-related adverse events. The newer formulation no longer includes alcohol, using polysorbate 80 along with refrigeration and smaller volumes to prevent anidulafungin from coming out of solution. It can also now be infused over 90 – 180 min, depending on dose, instead of 180 – 360 min. These modifications greatly improve the practicality of infusing anidulafungin to critically ill patients where intravenous access is often limited and drug compatibility can be problematic. With respect to drug interactions, anidulafungin is differentiated from caspofungin and micafungin in that it has no documented interactions through the CYP system pathway or hepatic transport protein OATP-1B1, the latter of which is potentially responsible for the drug interaction between caspofungin and cyclosporine. Anidulafungin has also demonstrated similar adverse events to its comparators and is generally well tolerated.

Clinical and animal studies have demonstrated anidulafungin’s efficacy in esophageal candidiasis, invasive candidiasis and candidemia. There may also be a role for anidulafungin in combination with non-echinocandin agents for the treatment of invasive aspergillosis, but animal models provide mixed conclusions and the anticipated combination study with voriconazole is still ongoing.

At most hospitals, Candida infections still respond favorably to optimal doses of fluconazole, which should remain a first consideration as it is very well tolerated and inexpensive. That being said, the increasing frequency of azole-resistant Candida species causing serious infections in critically ill and immunocompromised patients makes the decision to initially use an echinocandin such as anidulafungin more straightforward. The choice of specifically which echinocandin, however, is more difficult and will probably be based on patient characteristics (e.g., hepatic dysfunction, drug interactions) and cost to the hospital.