Anidulafungin (DB00362): A Comprehensive Pharmacological and Clinical Review

I. Executive Summary & Key Characteristics

Anidulafungin is a second-generation, semi-synthetic echinocandin antifungal agent administered intravenously for the treatment of serious Candida infections. It is distinguished within its class by a unique, non-enzymatic degradation pathway, which confers a highly favorable drug interaction profile and obviates the need for dose adjustments in patients with hepatic or renal impairment.[1] This characteristic positions anidulafungin as a first-line therapeutic option, particularly in critically ill patients with complex comorbidities and polypharmacy.

Key attributes of anidulafungin include its potent and selective inhibition of fungal (1→3)-β-D-glucan synthase, an enzyme essential for fungal cell wall integrity but absent in mammals, which results in fungicidal activity against most Candida species.[1] Its pharmacokinetic profile is characterized by a long terminal half-life of 40–50 hours, low systemic clearance, and a unique metabolic profile dominated by slow chemical degradation at physiological temperature and pH, independent of hepatic cytochrome P450 (CYP450) and renal elimination pathways.[1]

Clinically, anidulafungin is indicated for the treatment of candidemia, intra-abdominal abscess, peritonitis, and esophageal candidiasis in adults.[6] Its approval extends to pediatric patients aged one month and older for invasive candidiasis.[6] The drug is generally well-tolerated, with the most frequently reported adverse effects being hypokalemia, gastrointestinal disturbances (nausea, diarrhea), and pyrexia.[7] While it carries important warnings regarding the potential for hepatotoxicity and infusion-related hypersensitivity reactions, it does not have a black box warning from the U.S. Food and Drug Administration (FDA), reflecting a manageable risk profile in clinical practice.[11] Its minimal potential for drug-drug interactions makes it a valuable agent in the management of invasive fungal infections in complex patient populations, solidifying its place as a first-line therapy for invasive candidiasis.[13]

II. Chemical Identity and Pharmaceutical Formulation

Nomenclature and Identifiers

Anidulafungin is the established generic name for this small molecule antifungal agent.[1] It is marketed globally under several brand names, most notably

Eraxis in the United States and Russia, and Ecalta in Europe.[17] During its development phase at Eli Lilly and Company and later Vicuron Pharmaceuticals, it was known by the developmental code LY303366.[1]

For precise identification in scientific and regulatory databases, anidulafungin is assigned several unique identifiers:

• CAS (Chemical Abstracts Service) Number: 166663-25-8 [1]
• DrugBank ID: DB00362 [1]
• UNII (Unique Ingredient Identifier): 9HLM53094I [1]
• ATC Code: J02AX06 [1]

Chemical Structure and Classification

Anidulafungin is classified as an echinocandin antifungal, a structural subclass of lipopeptides.[2] Chemically, it is a semi-synthetic, cyclic hexapeptide distinguished by an N-linked acyl lipid side chain. The formal IUPAC name is N--11,20,21,25-tetrahydroxy-3,15-bis-26-methyl-2,5,8,14,17,23-hexaoxo-1,4,7,13,16,22-hexaazatricyclo[22.3.0.09,13]heptacosan-18-yl]- 4-{4-[4-(pentyloxy)phenyl]phenyl}benzamide.[1] A more common chemical name is 1--4-yl]carbonyl]-L-ornithine]echinocandin B.[2]

The drug is produced via a semi-synthetic process that begins with echinocandin B, a natural lipopeptide obtained from the fermentation of the fungus Aspergillus nidulans or the related species Aspergillus rugulosus.[1] This starting material undergoes enzymatic deacylation, where the native linoleoyl side chain is cleaved by a deacylase enzyme derived from the bacterium

Actinoplanes utahensis. The resulting peptide core is then subjected to a series of synthetic chemical steps, including a reacylation process, to attach the unique terphenyl side chain that defines the anidulafungin molecule.[1]

Physicochemical Properties

• Molecular Formula: C58​H73​N7​O17​ [1]
• Molecular Weight: Approximately 1140.24 g/mol [1]
• Appearance and Solubility: Anidulafungin is a white to off-white powder. It is characterized as practically insoluble in water and only slightly soluble in ethanol. For laboratory use, it is soluble in dimethyl sulfoxide (DMSO) to a concentration of 5 mM.[2]

Pharmaceutical Formulation and Excipients

Anidulafungin is supplied commercially as a sterile, lyophilized (freeze-dried) powder for concentrate for solution for infusion.[2] It is available in single-use vials containing either 50 mg or 100 mg of the active drug.[7]

In addition to the active pharmaceutical ingredient, the formulation contains several inactive ingredients (excipients) that are critical for the drug's stability, solubility, and administration. These include fructose (50 mg in 50 mg vial, 119 mg in 100 mg vial), mannitol (250 mg), polysorbate 80 (125 mg), tartaric acid, and sodium hydroxide and/or hydrochloric acid for pH adjustment.[2]

The choice of these excipients introduces critical safety considerations that are entirely independent of anidulafungin's primary pharmacological activity. The presence of fructose in the formulation leads to a direct and absolute contraindication in patients with Hereditary Fructose Intolerance (HFI).[24] This rare genetic disorder prevents the proper metabolism of fructose, and intravenous administration to affected individuals can precipitate a life-threatening metabolic crisis, including severe hypoglycemia, hypophosphatemia, lactic acidosis, and acute hepatic failure.[7] This necessitates a specific and careful patient history regarding HFI symptoms (e.g., nausea, vomiting, abdominal pain after consuming sugar) before anidulafungin can be safely administered.[8] The risk is particularly acute in the pediatric population, especially in infants and young children under two years of age, who may have undiagnosed HFI, making this a crucial point of clinical vigilance.[8]

Furthermore, the inclusion of polysorbate 80 as a solubilizing agent raises concerns for use in neonates. While toxicity has not been directly reported with the anidulafungin formulation, high doses of polysorbate 80 administered parenterally to low-birth-weight infants have been associated with a severe toxicity syndrome characterized by thrombocytopenia, renal dysfunction, hepatomegaly, cholestasis, and metabolic acidosis.[25] This formulation component contributes to the cautious approach and lack of approval for anidulafungin use in neonates (<1 month of age).

III. Pharmacology

A. Mechanism of Action

Anidulafungin exerts its antifungal effect through the potent and selective inhibition of the enzyme (1→3)-β-D-glucan synthase.[1] This enzyme is essential for the synthesis of 1,3-β-D-glucan, a fundamental structural polysaccharide that constitutes 30% to 60% of the cell wall in many pathogenic fungi, including

Candida and Aspergillus species.[27] By non-competitively inhibiting this enzyme, anidulafungin disrupts the formation of this critical polymer, leading to a severely weakened and defective fungal cell wall.[4] The compromised cell wall is unable to withstand osmotic pressure, resulting in cellular lysis and, ultimately, fungal cell death.[4]

The clinical safety and high therapeutic index of anidulafungin are rooted in its selective toxicity. The target enzyme, (1→3)-β-D-glucan synthase, is a vital component of the fungal cell but is entirely absent in mammalian cells.[1] This specificity ensures that the drug's activity is directed exclusively against the fungal pathogen, minimizing off-target effects on the human host.

B. Pharmacodynamics

The pharmacodynamic profile of anidulafungin is characterized by concentration-dependent antifungal activity. It is generally fungicidal against most Candida species and fungistatic against Aspergillus species.[30]

A defining and highly unusual pharmacodynamic feature of anidulafungin is its primary mechanism of clearance. Rather than being metabolized by host enzymes, it undergoes slow, spontaneous chemical degradation at physiological body temperature (37∘C) and pH.[1] This non-enzymatic hydrolysis process opens the cyclic peptide ring structure, converting anidulafungin into a primary degradant that lacks any antifungal activity.[1] The

in vitro half-life of this degradation process under physiological conditions is approximately 24 hours.[2] This inherent chemical instability is a central element of its pharmacokinetic profile and is paradoxically responsible for its most significant clinical advantages.

C. Pharmacokinetics (ADME)

The pharmacokinetic profile of anidulafungin is predictable, with low intersubject variability (<25% coefficient of variation) and dose-proportional systemic exposures.[2] Its most notable characteristic is its clearance pathway via chemical degradation, which makes its disposition independent of hepatic and renal function and results in a minimal potential for drug-drug interactions.

Absorption

Anidulafungin is administered exclusively by intravenous infusion, which results in 100% bioavailability.[1] Following the administration of a loading dose (twice the maintenance dose), steady-state plasma concentrations are rapidly achieved on the first day of therapy, with a plasma accumulation factor of approximately 2.[2]

Distribution

The distribution of anidulafungin is characterized by a short initial distribution half-life of 0.5 to 1 hour.[2] It has a volume of distribution (

Vd​) of 30–50 L, which is similar in magnitude to the total body fluid volume, suggesting distribution into tissues.[2] Anidulafungin is extensively bound to human plasma proteins, with reported binding of 84% to over 99%.[1]

Preclinical studies in rats have demonstrated rapid and extensive distribution into tissues, particularly those organs most commonly affected by invasive mycoses. Peak drug concentrations were achieved within 30 minutes in most tissues, and the total drug exposure (AUC) in the liver, lung, kidney, and spleen was found to be 9- to 12-fold higher than the exposure in plasma.[32] While the drug appears to persist longer in these key tissues than in plasma, penetration into the central nervous system (CNS) is limited, with only low levels of radioactivity detected in the cerebrospinal fluid (CSF) and brain tissue.[32]

Metabolism

The metabolism of anidulafungin is unique among antifungals and is the cornerstone of its predictable clinical behavior. Hepatic metabolism has not been observed.[1] The drug is not a substrate, inducer, or inhibitor of any cytochrome P450 (CYP450) isoenzymes at clinically relevant concentrations.[2]

Instead of enzymatic biotransformation, its clearance is driven by slow, non-enzymatic chemical degradation at physiological temperature and pH. This process of chemical hydrolysis opens the cyclic peptide structure to form a ring-opened peptide that is devoid of antifungal activity.[2] This primary degradant is then further broken down into smaller peptidic fragments and eliminated.[2] This clearance mechanism, being independent of the body's major drug-metabolizing systems, is the direct reason for anidulafungin's lack of clinically significant drug interactions and the absence of a need for dose adjustments in patients with organ dysfunction.

Excretion

Elimination of anidulafungin and its degradants occurs primarily via the biliary route into the feces. Following administration of a single radiolabeled dose to healthy subjects, approximately 30% of the radioactive dose was recovered in the feces over a period of nine days. Intact, unchanged anidulafungin accounted for less than 10% of the material recovered in feces, indicating that the majority is eliminated as degradation products.[1]

Renal excretion is a negligible pathway for elimination. Less than 1% of the administered dose is excreted in the urine.[1] Plasma concentrations of the drug typically fall below the lower limit of quantitation by six days after a dose.[2]

Key Pharmacokinetic Parameters

Anidulafungin exhibits a low systemic clearance of approximately 1 L/h.[2] Its elimination profile is multiphasic, with a predominant elimination half-life of approximately 24–27 hours and a longer terminal elimination half-life of 40–50 hours.[1] This long half-life profile supports convenient once-daily dosing.

Table 1: Summary of Steady-State Pharmacokinetic Parameters of Anidulafungin in Adults

Dose Regimen (LD/MD, mg)	Cmax,ss​ (mg/L)	AUCss​ (mg·h/L)	Clearance (L/h)	Terminal Half-Life (t1/2​, h)
100 / 50	4.2	55.2	0.84	43.2
200 / 100	7.2 - 8.6	110.3 - 111.8	0.94	26.5 - 52

Data compiled from healthy subjects and patients in clinical studies. LD = Loading Dose; MD = Maintenance Dose; Cmax,ss​ = Steady-state peak concentration; AUCss​ = Steady-state area under the curve; ss = steady state. Sources:.[2]

IV. Clinical Efficacy and Spectrum of Activity

A. Approved Clinical Indications

Anidulafungin is approved by regulatory agencies for the treatment of several serious fungal infections caused by Candida species. Its primary indications are:

• Candidemia and Other Forms of Invasive Candidiasis: Anidulafungin is indicated for the treatment of candidemia (fungal infection in the bloodstream) and other deep-tissue Candida infections, including intra-abdominal abscess and peritonitis. This indication is approved for both adult and pediatric patients aged one month and older.[6]
• Esophageal Candidiasis: It is also indicated for the treatment of esophageal candidiasis, a mucosal infection of the esophagus, in adult patients.[1]

Therapy may be initiated empirically before culture results are available, but treatment should be adjusted accordingly once the causative organism and its susceptibilities are identified.[6]

B. Limitations of Use

The product labeling for anidulafungin specifies several important limitations of use based on the populations and conditions studied in clinical trials:

• Specific Severe Infections: Anidulafungin has not been studied in patients with endocarditis (infection of the heart valves), osteomyelitis (bone infection), or meningitis (infection of the CNS) due to Candida. Therefore, its efficacy in these severe manifestations of disseminated disease is unknown.[1]
• Neutropenic Patients: The efficacy of anidulafungin has not been established in neutropenic patients (those with very low white blood cell counts), as this population was not studied in sufficient numbers during pivotal trials.[1]
• Relapse in Esophageal Candidiasis: Anidulafungin is associated with high relapse rates in patients treated for esophageal candidiasis, particularly those with underlying HIV infection. For these patients, long-term suppressive antifungal therapy may be considered after the initial treatment course is completed.[6]

C. Spectrum of Antimicrobial Activity

Anidulafungin possesses a targeted spectrum of activity, demonstrating potent efficacy against specific fungal pathogens while lacking activity against others.

Active Against:

• Candida Species: Anidulafungin exhibits potent in vitro activity against a broad range of Candida species, including the most common cause of invasive disease, C. albicans, as well as C. glabrata, C. parapsilosis, and C. tropicalis.[5] A key clinical advantage is its activity against Candida isolates that have developed resistance to other antifungal classes, such as azoles (e.g., fluconazole) and polyenes (e.g., amphotericin B).[21]
• Aspergillus Species: The drug demonstrates in vitro activity against Aspergillus species, where it is typically fungistatic.[16] While not a primary monotherapy for aspergillosis, there is evidence suggesting it may have a role in treating invasive Aspergillus infections when used in combination with other agents, such as voriconazole.[1]

Not Active Against:

The echinocandin class as a whole, including anidulafungin, is intrinsically not active against several important fungal pathogens. These include:

• Cryptococcus neoformans
• Trichosporon species
• Fusarium species
• Zygomycetes (e.g., Mucor, Rhizopus).[5]

This inherent resistance pattern is critical for guiding appropriate empiric therapy; anidulafungin should not be used if these organisms are suspected pathogens.

A notable phenomenon in laboratory testing is the "paradoxical effect" or "Eagle effect" observed when echinocandins are tested against Aspergillus species in vitro. This effect is characterized by an apparent increase in fungal metabolic activity or growth at drug concentrations well above the inhibitory level.[34] This artifact can make standard Minimum Inhibitory Concentration (MIC) testing, which measures growth inhibition, difficult to interpret and potentially misleading. Consequently, the clinically relevant susceptibility endpoint for echinocandins against molds is the Minimum Effective Concentration (MEC), a value determined by microscopic examination of hyphal morphology.[34] This distinction is vital for clinicians and microbiologists, as a high MIC value for anidulafungin against an

Aspergillus isolate may represent this in vitro paradox rather than true clinical resistance. Therefore, therapeutic decisions for mold infections should be guided by clinical trial data, practice guidelines, and MEC testing where available, rather than relying solely on standard MIC results.

V. Dosage and Administration

The administration of anidulafungin requires strict adherence to approved dosing regimens, preparation procedures, and infusion rates to ensure both efficacy and patient safety.

A. Dosing Regimens

Dosing is indication- and population-specific and involves an initial loading dose to rapidly achieve therapeutic concentrations, followed by a once-daily maintenance dose.

• Adults - Candidemia and Other Invasive Candida Infections:
• Loading Dose: A single 200 mg dose administered on Day 1.
• Maintenance Dose: 100 mg administered once daily thereafter.[6]
• Adults - Esophageal Candidiasis:
• Loading Dose: A single 100 mg dose administered on Day 1.
• Maintenance Dose: 50 mg administered once daily thereafter.[17]
• Pediatric Patients (1 month to < 18 years) - Invasive Candidiasis:
• Loading Dose: A single 3.0 mg/kg dose (not to exceed 200 mg) administered on Day 1.
• Maintenance Dose: 1.5 mg/kg (not to exceed 100 mg) administered once daily thereafter.[8]

Treatment Duration: For invasive candidiasis, antifungal therapy should generally continue for at least 14 days after the last positive blood culture and the resolution of clinical signs and symptoms.[6] For esophageal candidiasis, patients should be treated for a minimum of 14 days and for at least 7 days following the resolution of symptoms.[17]

B. Preparation and Intravenous Administration

Anidulafungin must be prepared in a two-step aseptic process of reconstitution followed by dilution.

1. Reconstitution: The lyophilized powder in the vial must first be reconstituted with Sterile Water for Injection.

• For a 50 mg vial, add 15 mL of Sterile Water for Injection.
• For a 100 mg vial, add 30 mL of Sterile Water for Injection.
• This yields a reconstituted solution with a concentration of 3.33 mg/mL.[7]

2. Dilution: The required volume of the reconstituted solution is then withdrawn and transferred into an IV bag containing either 5% Dextrose Injection, USP (D5W) or 0.9% Sodium Chloride Injection, USP (Normal Saline). The solution must be diluted to a final concentration of 0.77 mg/mL.[22]
3. Administration Rate: The final diluted solution must be administered via intravenous infusion at a rate that does not exceed 1.1 mg/minute.[12] This corresponds to an infusion rate of 1.4 mL/minute or 84 mL/hour for the correctly diluted solution.

The maximum infusion rate is a critical safety parameter, not merely a guideline. This restriction is directly linked to the prevention of potentially severe, histamine-mediated infusion-related reactions.[7] Rapid administration of anidulafungin can trigger mast cell degranulation and the release of histamine, leading to symptoms such as rash, urticaria, flushing, pruritus, dyspnea, bronchospasm, and hypotension.[12] Adherence to the prescribed infusion duration is therefore a primary strategy for mitigating this risk. This necessitates careful programming of infusion pumps and clear communication between pharmacy and nursing staff to ensure the drug is never administered as a rapid IV push or bolus, which could provoke a serious adverse event.

Storage: The reconstituted solution (in the vial) is chemically and physically stable for up to 24 hours at room temperature (25°C or 77°F) prior to dilution. The final diluted infusion solution is stable for up to 48 hours at room temperature and must not be frozen.[12]

Table 2: Recommended Dosing and Administration Regimens for Anidulafungin

Indication	Patient Population	Loading Dose (Day 1)	Maintenance Dose (Daily)	Minimum Infusion Duration
Candidemia / Invasive Candidiasis	Adults	200 mg	100 mg	90 minutes (100 mg dose) 180 minutes (200 mg dose)
Candidemia / Invasive Candidiasis	Pediatrics (≥1 month)	3.0 mg/kg (max 200 mg)	1.5 mg/kg (max 100 mg)	Dose-dependent; rate must not exceed 1.1 mg/min
Esophageal Candidiasis	Adults	100 mg	50 mg	45 minutes (50 mg dose) 90 minutes (100 mg dose)

Infusion durations are calculated based on the maximum infusion rate of 1.1 mg/min (equivalent to 1.4 mL/min) for the final 0.77 mg/mL solution. Sources:.[7]

VI. Safety and Tolerability Profile

Anidulafungin is generally well-tolerated, with a safety profile consistent with the echinocandin class. Adverse events are typically mild to moderate in severity.

A. Adverse Drug Reactions

The most frequently observed adverse reactions in clinical trials for invasive candidiasis vary slightly by patient population and indication.

• Most Common Adverse Reactions (incidence ≥10% in adults):
• Metabolic: Hypokalemia (up to 25%) [7]
• Gastrointestinal: Nausea (up to 24%), Diarrhea (up to 18%), Vomiting (up to 18%) [7]
• General: Pyrexia (fever) (up to 18%) [7]
• Psychiatric: Insomnia (up to 15%) [7]
• Vascular: Hypotension (up to 15%), Deep vein thrombosis (up to 10%) [7]
• Respiratory: Dyspnea (up to 12%), Pleural effusion (up to 10%) [10]
• Common Adverse Reactions (incidence 1-10%):
• Hepatic: Increased hepatic enzymes (ALT, AST, alkaline phosphatase), increased blood bilirubin, cholestasis [7]
• Nervous System: Headache, convulsion, confusional state [7]
• Hematologic: Anemia, increased WBCs [7]
• Dermatologic: Rash, pruritus [10]

Serious Adverse Events

While infrequent, several serious adverse reactions warrant clinical attention:

• Hepatotoxicity: Laboratory abnormalities in liver function tests have been observed. While often transient, there have been isolated reports of clinically significant hepatic dysfunction, hepatitis, or hepatic failure in patients receiving anidulafungin, particularly those with serious underlying medical conditions and receiving multiple concomitant medications. A definitive causal relationship to anidulafungin has not been established, but patients who develop abnormal liver tests during therapy should be monitored for evidence of worsening hepatic function.[7]
• Hypersensitivity and Anaphylaxis: Serious hypersensitivity reactions, including anaphylaxis and anaphylactic shock, have been reported with the use of anidulafungin. If such a reaction occurs, the drug must be discontinued immediately and appropriate treatment administered.[8] As previously noted, infusion-related reactions (e.g., rash, urticaria, flushing, dyspnea, hypotension), which are possibly histamine-mediated, are a key concern and are mitigated by adhering to the recommended slow infusion rate.[7]

B. Warnings, Precautions, and Contraindications

Regulatory Status and Warnings

Anidulafungin does not carry a black box warning from the U.S. FDA.[5] The absence of this highest-level warning, despite the presence of significant warnings for hepatotoxicity and anaphylaxis in the product labeling, is a notable regulatory assessment of the drug's overall risk-benefit profile. Black box warnings are reserved for adverse reactions that are severe, potentially fatal, or require specific risk mitigation strategies beyond standard clinical practice. The FDA's decision suggests that while the risks of liver injury and anaphylaxis are real and require clinical vigilance, their incidence and manageability (e.g., monitoring liver function tests, discontinuing the drug if a reaction occurs) do not meet the threshold for the most stringent warning. This provides important context for clinicians, framing the safety profile as generally favorable but with specific, identifiable risks that must be monitored, rather than as a drug with an inherently high and unavoidable level of danger.

Contraindications

Anidulafungin is contraindicated in patients with:

1. Known hypersensitivity to anidulafungin, any of its components, or any other drug in the echinocandin class (e.g., caspofungin, micafungin).[12]
2. Known or suspected Hereditary Fructose Intolerance (HFI), due to the presence of fructose as an excipient in the formulation.[24]

C. Overdose Information

Experience with anidulafungin overdose is limited. In one clinical trial, a single 400 mg dose was inadvertently administered as a loading dose without any clinical adverse events being reported.[5] Preclinical studies in rats found the maximum non-lethal dose to be 50 mg/kg, a dose equivalent to 5 to 10 times the recommended daily human dose based on relative body surface area.[5] In the event of an overdose, general supportive measures should be employed as necessary.[23]

Table 3: Incidence of Common Adverse Reactions (≥5%) in Adults with Candidemia

Adverse Reaction	Anidulafungin 100 mg (%)	Fluconazole (%)
Hypokalemia	10	13
Diarrhea	10	8
Nausea	8	7
Vomiting	6	6
Pyrexia	6	5
Increased ALT	5	3
Increased AST	4	3

Data from the pivotal comparative trial in patients with candidemia/invasive candidiasis. Source:.[7]

VII. Drug-Drug Interactions

A key clinical advantage of anidulafungin is its exceptionally low potential for clinically significant drug-drug interactions (DDIs). This favorable profile is a direct consequence of its unique clearance mechanism—slow, non-enzymatic chemical degradation—which completely bypasses the hepatic cytochrome P450 (CYP450) enzyme system and renal excretion pathways that are responsible for the metabolism and elimination of most drugs.[2] Anidulafungin is not a substrate, inducer, or inhibitor of CYP450 isoenzymes, making it a predictable agent in patients receiving multiple medications.[2]

Formal drug interaction studies have been conducted with several commonly co-administered medications, confirming this lack of interaction.

• Immunosuppressants:
• Cyclosporine (CYP3A4 substrate): Co-administration did not significantly alter the peak concentration (Cmax​) of anidulafungin, although the total exposure (AUC) increased by a modest 22%. The pharmacokinetics of cyclosporine were not affected. No dosage adjustment is required for either drug.[2]
• Tacrolimus (CYP3A4 substrate): Co-administration did not result in any significant alteration in the pharmacokinetic parameters of either anidulafungin or tacrolimus. No dosage adjustment is required.[2]
• Other Antifungals:
• Voriconazole (CYP2C19, CYP2C9, CYP3A4 inhibitor and substrate): The steady-state pharmacokinetics of both anidulafungin and voriconazole were unaltered during co-administration. No dosage adjustment is needed.[2]
• Liposomal Amphotericin B: Co-administration did not significantly affect the pharmacokinetics of anidulafungin. No dosage adjustment is required.[23]
• Potent Enzyme Inducers:
• Rifampicin (potent CYP450 inducer): Population pharmacokinetic analysis showed that co-administration with rifampicin did not significantly alter the pharmacokinetics of anidulafungin. No dosage adjustment is required.[2] This is a critical differentiating feature from caspofungin, which requires a dose increase when co-administered with potent inducers like rifampicin.

While pharmacokinetic interactions are minimal, a few pharmacodynamic or other interactions have been noted:

• Saccharomyces boulardii: As an antifungal agent, anidulafungin is expected to inhibit the activity of this probiotic yeast. Concurrent use should be avoided.[7]
• Voclosporin: There is a potential for additive toxicity (nephrotoxicity and/or ototoxicity) when co-administered with this calcineurin inhibitor. Close monitoring is advised if combination therapy is necessary.[7]

Table 4: Summary of Anidulafungin Drug Interaction Studies and Dosing Recommendations

Co-administered Drug	Known Mechanism/Substrate	Effect on Anidulafungin PK	Effect on Co-administered Drug PK	Clinical Recommendation
Cyclosporine	CYP3A4 Substrate	AUC increased by 22%	No significant effect	No dose adjustment required for either drug
Tacrolimus	CYP3A4 Substrate	No significant effect	No significant effect	No dose adjustment required for either drug
Voriconazole	CYP Inhibitor/Substrate	No significant effect	No significant effect	No dose adjustment required for either drug
Rifampicin	Potent CYP450 Inducer	No significant effect	Not studied	No dose adjustment required for anidulafungin
Liposomal Amphotericin B	Antifungal	No significant effect	Not studied	No dose adjustment required for anidulafungin
Saccharomyces boulardii	Probiotic Yeast	N/A	Efficacy may be decreased	Avoid combination
Voclosporin	Calcineurin Inhibitor	N/A	Potential for increased toxicity	Monitor closely; modify therapy if needed

PK = Pharmacokinetics; AUC = Area under the curve; N/A = Not applicable. Sources:.[2]

VIII. Use in Specific Populations

The clinical use of anidulafungin is well-defined across various patient populations, with its unique pharmacokinetic profile simplifying its application in many complex scenarios.

A. Renal and Hepatic Impairment

Anidulafungin's clearance pathway via non-enzymatic chemical degradation renders it effectively independent of both renal and hepatic function, a profound clinical advantage that makes it an "organ-proof" antifungal. Numerous studies and regulatory documents confirm that no dosage adjustments are required for patients with any degree of renal insufficiency, including those with end-stage renal disease requiring hemodialysis.[13] The drug is not dialyzable, so it can be administered without regard to the timing of dialysis sessions.[2]

Similarly, no dosage adjustments are necessary for patients with any degree of hepatic impairment, including mild, moderate, or severe (Child-Pugh Class A, B, or C) insufficiency.[23] This is a direct result of its non-hepatic clearance.[2] This characteristic dramatically simplifies prescribing for critically ill patients, who often present with fluctuating or compromised organ function. It eliminates the need for dose calculations based on creatinine clearance or Child-Pugh scores, reducing the cognitive burden on clinicians and the potential for dosing errors. This provides a clear therapeutic advantage over other antifungals, such as caspofungin (which requires dose reduction in moderate hepatic impairment) and many azoles, positioning anidulafungin as a preferred echinocandin for patients with established or evolving liver disease.[13]

B. Pediatric Population

• Approval and Dosing: Anidulafungin is approved for the treatment of invasive candidiasis in pediatric patients aged one month to less than 18 years.[6] The recommended weight-based dosing regimen (3.0 mg/kg loading dose followed by 1.5 mg/kg maintenance dose) has been shown to produce systemic drug exposures in children that are comparable to those achieved in adults receiving the standard fixed-dose regimen.[36]
• Neonates (<1 month): The safety and efficacy of anidulafungin have not been established in neonates.[8] There are significant concerns in this population. Nonclinical models suggest that higher doses may be needed to achieve adequate CNS penetration for treating disseminated candidiasis with CNS involvement, a common occurrence in neonates.[8] Furthermore, the formulation contains polysorbate 80, an excipient linked to severe toxicity in low-birth-weight infants, adding to the caution in this vulnerable group.[8]

C. Geriatric Population

Clinical studies have shown no significant differences in the pharmacokinetics or safety profile of anidulafungin in geriatric patients (≥65 years) compared to younger adults. Although clearance was observed to be slightly lower in the elderly, the difference was not considered clinically relevant. Therefore, no dosage adjustment is required based on age.[2]

D. Pregnancy and Lactation

Pregnancy

• Regulatory Status: Anidulafungin is classified as Pregnancy Category B3 by the Australian Therapeutic Goods Administration (TGA). The U.S. FDA has phased out its letter-based pregnancy categories, and it is now listed as "Not Assigned".[40]
• Clinical Data: There are no adequate and well-controlled studies on the use of anidulafungin in pregnant women.[23]
• Animal Data: Animal reproduction studies have raised concerns. In rabbits, doses that produced maternal toxicity were also associated with fetotoxicity, including reduced fetal weights and incomplete bone ossification.[33] In rats, the drug was shown to cross the placental barrier and was detected in fetal plasma.[31]
• Recommendation: Due to the lack of human data and the findings in animal studies, anidulafungin should not be used during pregnancy unless the potential benefit to the mother clearly outweighs the potential risk to the fetus.[23]

Lactation

• Clinical Data: Data on anidulafungin in human milk is limited but reassuring. A case report of a postpartum woman receiving 100 mg daily found that the drug is excreted into breast milk at very low levels. The peak milk concentration was 0.24 mg/L, and the drug became undetectable 38 hours after the final dose. No adverse effects were observed in the breastfed infant.[41]
• Recommendation: Because the amount of drug ingested by a nursing infant is expected to be small and unlikely to cause adverse effects, maternal use of anidulafungin is not considered a reason to discontinue breastfeeding. The decision should be made by weighing the benefits of breastfeeding for the child against the mother's clinical need for the drug.[23]

IX. Comparative Analysis with Other Echinocandins (Caspofungin, Micafungin)

While the three clinically available echinocandins—anidulafungin, caspofungin, and micafungin—share a common mechanism of action and a similar spectrum of activity, they are not therapeutically interchangeable. Subtle but significant differences in their pharmacokinetics, metabolism, dosing requirements, drug interaction profiles, and approved indications create distinct clinical niches, allowing for tailored therapy based on specific patient characteristics.

All three agents are available only as intravenous formulations, are highly effective against most Candida species, and have an excellent overall safety profile.[28] However, a comparative analysis reveals key differentiators.

• Anidulafungin's Niche ("Simple and Safe"): Anidulafungin's primary advantage is its unique non-enzymatic degradation, which eliminates hepatic metabolism and the potential for CYP450-mediated drug interactions.[28] This makes it an ideal choice for adult patients with significant comorbidities, particularly those with hepatic impairment or those on complex medication regimens involving CYP450 substrates, inhibitors, or inducers. It requires a loading dose. Its approval in pediatrics is more recent compared to the other agents.[8]
• Caspofungin's Niche ("The Workhorse"): As the first approved echinocandin, caspofungin has the longest history of clinical use. It undergoes hepatic metabolism and requires a dose reduction in patients with moderate hepatic impairment.[28] It has clinically significant interactions with potent CYP450 inducers like rifampin (requiring a dose increase) and with the immunosuppressant cyclosporine.[28] It has established indications for invasive candidiasis, salvage therapy for invasive aspergillosis, and empiric therapy in febrile neutropenia.[28]
• Micafungin's Niche ("Pediatric and Prophylaxis Specialist"): Micafungin is distinguished by its broad pediatric approval, which includes neonates, and its unique indication for the prophylaxis of Candida infections in hematopoietic stem cell transplant recipients.[28] It is metabolized in the liver but to a lesser extent via CYP3A4, with some potential to increase concentrations of drugs like sirolimus.[28] A key practical advantage is that it does not require a loading dose, which can simplify the initiation of therapy.[14]

The choice among these agents is therefore a strategic clinical decision. For a critically ill adult with liver failure and polypharmacy, anidulafungin's predictable, organ-independent profile is highly advantageous. For a neonate with suspected candidemia or a patient requiring prophylaxis during a stem cell transplant, micafungin is the indicated choice. Caspofungin remains a valuable option, particularly in settings where its long-term efficacy and safety data are valued, provided its interaction and hepatic dosing considerations are managed.

Table 5: Comparative Profile of Anidulafungin, Caspofungin, and Micafungin

Feature	Anidulafungin	Caspofungin	Micafungin
Loading Dose Required	Yes (200 mg or 100 mg)	Yes (70 mg)	No
Primary Metabolism	Chemical Degradation (Non-enzymatic)	Hepatic (Hydrolysis, N-acetylation)	Hepatic (Enzymatic, minor CYP3A4)
Dose Adj. - Hepatic Impairment	No	Yes (Moderate Impairment)	No (but not studied in severe)
Dose Adj. - Renal Impairment	No	No	No
Key DDI (with CYP Inducers)	No interaction	Yes (requires dose increase)	No significant interaction
Approved for Neonates (<1 mo)	No	No	Yes
Prophylaxis Indication	No	No	Yes (HSCT patients)

Adj. = Adjustment; DDI = Drug-Drug Interaction; HSCT = Hematopoietic Stem Cell Transplant. Sources:.[14]

X. Regulatory and Commercial Overview

Development and Commercialization

Anidulafungin was originally discovered in the laboratories of Eli Lilly and Company and was subsequently developed by Vicuron Pharmaceuticals under the designation LY303366.[1] In 2005, Pfizer Inc. acquired Vicuron Pharmaceuticals and, with it, the rights to anidulafungin.[1] Pfizer brought the drug through the final stages of regulatory approval and continues to manufacture and market it globally.[16]

Regulatory Approval History

Anidulafungin has received marketing authorization from major regulatory agencies worldwide.

• U.S. Food and Drug Administration (FDA):
• Brand Name: Eraxis
• Approval Date: February 17, 2006
• Details: The initial New Drug Application (NDA 21-632) was approved for the 50 mg vial for the treatment of esophageal candidiasis. A separate NDA (21-948) for candidemia and other invasive Candida infections received priority review and was also approved. The 100 mg vial was approved on November 14, 2006.[16]
• European Medicines Agency (EMA):
• Brand Name: Ecalta
• Approval Date: September 20, 2007
• Details: Ecalta was granted a marketing authorization valid throughout the European Union for the treatment of invasive candidiasis in adult and, later, pediatric patients.[17]

WHO Recognition

In recognition of its efficacy and safety profile for treating serious fungal infections, anidulafungin is included on the World Health Organization's (WHO) Model List of Essential Medicines. It is listed under the "Antifungal medicines" section for the indication of systemic or invasive candidiasis.[16]

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