The safety of anidulafungin

The echinocandins are a new class of antifungal that have shown promising results in treating a variety of fungal infections. Anidulafungin is the newest approved echinocandin and may have some advantages over existing antifungals. It has activity against a broad range of fungi. It is unique because it undergoes a process of slow chemical degradation rather than being metabolised. Studies evaluating the use of anidulafungin in combination with other commonly used drugs have not demonstrated any significant drug-drug interactions or adverse events. Thus far, anidulafungin appears to have an excellent safety profile with few adverse events. Based on early clinical experience, it appears that anidulafungin will be a valuable and safe asset in the management of serious and difficult-to-treat fungal infections.     

Safety and pharmacokinetics of coadministered voriconazole and anidulafungin

There is considerable interest in combining echinocandin and triazole antifungal agents for treatment of invasive fungal infections; however, information is needed regarding the tolerability and potential for pharmacokinetic interactions. Anidulafungin is a semisynthetic echinocandin, and voriconazole is an extended-spectrum triazole. In a random sequence, 17 subjects received anidulafungin with placebo, voriconazole with placebo, and anidulafungin with voriconazole. Anidulafungin was administered intravenously: 200 mg on day 1, then 100 mg/d on days 2 through 4. Voriconazole was administered orally: 400 mg every 12 hours on day 1, then 200 mg every 12 hours on days 2 to 4. No dose-limiting toxicities or serious adverse events occurred, and all adverse events were mild and consistent with the known safety profiles of both drugs. Pharmacokinetic parameters were not affected by coadministration. The geometric mean ratio (90% confidence interval) of the combination/drug alone for AUC(SS) was 97.4% (94.9-99.9), 97.4% (92.1-103.0), and 94.4% (87.0-102.5) for anidulafungin, voriconazole, and the voriconazole metabolite, respectively.     

Assessment of the safety and pharmacokinetics of anidulafungin when administered with cyclosporine

Anidulafungin is a novel antifungal agent of the echinocandin class that is intended for the treatment of invasive fungal disease. It is likely that anidulafungin will be coadministered with cyclosporine. In vitro studies and clinical studies were performed to evaluate the effect of anidulafungin on cyclosporine metabolism and to investigate the safety and pharmacokinetics of anidulafungin when concomitantly administered with cyclosporine. The potential for anidulafungin to inhibit the metabolism of cyclosporine was evaluated by pooled human hepatic microsomal protein fractions in vitro, incubating 3H-cyclosporine with different concentrations of anidulafungin. The safety of coadministration and the effects of cyclosporine on the pharmacokinetics of anidulafungin were assessed in a multiple-dose, open-label clinical study of 12 healthy volunteers. Subjects received a 200-mg intravenous loading dose of anidulafungin, followed by a daily 100-mg intravenous maintenance dose on days 2 through 8. An oral solution of cyclosporine (Neoral oral solution; 100 mg/mL) 1.25 mg/kg was also administered to subjects twice daily on days 5 through 8. In the in vitro study, the addition of anidulafungin had no effect on cyclosporine metabolism by human hepatic microsomal protein fractions. In the clinical study, no dose-limiting toxicities or serious adverse events occurred. A small increase in anidulafungin concentrations and drug exposure (22%) was observed after 4 days of dosing with cyclosporine and was not considered to be clinically relevant. The results support the concomitant use of anidulafungin and cyclosporine without the need for dosage adjustments of either drug.     

Lack of pharmacokinetic interaction between anidulafungin and tacrolimus

The safety and pharmacokinetics of anidulafungin coadministered with tacrolimus were investigated using a single-sequence, open-label design. Healthy volunteers received 5 mg tacrolimus orally on days 1 and 13 of the study. Anidulafungin (200 mg) was administered intravenously on day 4, followed by 100-mg doses on days 5 through 13. Key pharmacokinetic parameters, including C(max), AUC, t((1/2)), CL, and V(ss), were derived from concentration-time data. The 90% confidence intervals (CIs) of the ratios of mean pharmacokinetic parameters of anidulafungin plus tacrolimus to each drug alone were well within the 80% to 125% bioequivalence range, indicating no pharmacokinetic interaction. This ratio was 101.6 (90% CI: 92.77-111.22) for tacrolimus AUC(0-infinity) and 107.2 (90% CI: 105.1-109.4) for anidulafungin AUC(ss). The 2 drugs were well tolerated, and no drug-related serious adverse events were reported. Because of its lack of pharmacokinetic interaction with key immunosuppressive agents, anidulafungin is an important option for the prevention and treatment of invasive fungal infections in transplant recipients.     

The echinocandins

The changing pattern in fungal infections has driven the need to expand the targets of antifungal activity. The echinocandins are the newest addition to the arsenal against fungal infections. Three echinocandins have been approved by the United States Food and Drug Administration: caspofungin, micafungin, and anidulafungin. These agents have a broad spectrum of activity and are similar to each other with respect to in vitro activity against Candida sp, with micafungin and anidulafungin having similar minimum inhibitory concentrations (MICs) that are generally lower than the MIC of capsofungin. The MICs of the echinocandins are highest against Candida parapsilosis; however, whether this will affect clinical outcomes is unknown. Several case reports have identified clinical failure due to elevated MICs with caspofungin or micafungin against Candida albicans, Candida krusei, and C. parapsilosis. Resistance to the echinocandin class was present in some but not all of the isolates. Empiric therapy with one of the echinocandins for candidemia or invasive candidiasis in patients with neutropenia and those without neutropenia appears to be appropriate when one factors in mortality rate, the increasing frequency of non-albicans Candida infections, and the broad spectrum, safety, and fungicidal effect of the echinocandins. After speciation of the organism, continued therapy with an echinocandin can and should be reevaluated. The echinocandins demonstrate similar in vitro and in vivo activity against Aspergillus sp, but only caspofungin is approved for treatment in patients who are intolerant of or refractory to other therapies. Voriconazole and amphotericin B have demonstrated synergy with the echinocandins. The clinical response to combination therapy has been variable; however, the mortality rate appears to be lower with combination therapy than monotherapy. Large controlled trials are needed to determine the role of combination therapy for invasive aspergillosis. Micafungin and anidulafungin generally have a lower frequency of adverse reactions compared with caspofungin. Phlebitis (3.5-25% of patients) and elevated liver enzyme levels (1-15%) occur more often with caspofungin compared with micafungin and anidulafungin (< 8%). Overall, the three echinocandins are relatively safe and effective agents for the treatment of Candida infections.     

Anidulafungin: an evidence-based review of its use in invasive fungal infections

INTRODUCTION: Anidulafungin is a new echinocandin antifungal agent with indications for use in esophageal candidiasis and candidemia. The mortality and morbidity associated with fungal infections in healthcare facilities necessitates the development of new treatment options for these diseases. AIMS: This review assesses the pharmacology and evidence for the use of anidulafungin in the treatment of serious fungal infections. EVIDENCE REVIEW: There is substantial evidence that anidulafungin is a potent antifungal agent with activity against a broad range of fungal species. Likewise, evidence supports that anidulafungin is a well-tolerated antifungal agent. Clinical studies provide sufficient evidence for regulatory approval for esophageal candidiasis and candidemia, and limited evidence suggests that anidulafungin may be superior to fluconazole for candidemia and invasive candidiasis. The introduction of anidulafungin into clinical practice adds a third option for therapy in the echinocandin class. Research into its efficacy in other fungal infections is ongoing, and further studies into the impact of anidulafungin on economic outcomes will be beneficial. PLACE IN THERAPY: Current evidence supports the use of anidulafungin in the management of candidemia, esophageal candidiasis, and invasive candidiasis, as demonstrated by the successful results in large multicenter clinical trials.     

Anidulafungin

Anidulafungin is a novel antifungal agent which, like other echinocandins, inhibits beta-(1,3)-D-glucan synthase and disrupts fungal cell-wall synthesis. It has marked antifungal activity against a broad spectrum of Candida spp. and Aspergillus spp., including amphotericin B- and triazole-resistant strains. In clinical trials, anidulafungin has primarily been evaluated in patients with oesophageal and invasive candidiasis. Preliminary data are emerging for other indications such as invasive aspergillosis. In a large, multicentre, double-blind, double-dummy, randomised trial in patients with oesophageal candidiasis, intravenous anidulafungin 50 mg/day was as effective as oral fluconazole 100 mg/day regarding end-of-treatment rates of endoscopic cure and clinical and microbiological success. Duration of treatment was approximately 2-3 weeks, and patients in both groups received a loading dose of study drug (twice the daily maintenance dose) on day 1. Anidulafungin is generally well tolerated. Across the dosage range 50-100 mg/day, adverse events appear not to be dose- or infusion-related. In the largest clinical trial to date, the most common treatment-related adverse events were phlebitis/thrombophlebitis, headache, nausea, vomiting and pyrexia.     

Anidulafungin: an evidence-based review of its use in invasive fungal infections

Introduction:

Anidulafungin is a new echinocandin antifungal agent with indications for use in esophageal candidiasis and candidemia. The mortality and morbidity associated with fungal infections in healthcare facilities necessitates the development of new treatment options for these diseases.

Aims:

This review assesses the pharmacology and evidence for the use of anidulafungin in the treatment of serious fungal infections.

Evidence review:

There is substantial evidence that anidulafungin is a potent antifungal agent with activity against a broad range of fungal species. Likewise, evidence supports that anidulafungin is a well-tolerated antifungal agent. Clinical studies provide sufficient evidence for regulatory approval for esophageal candidiasis and candidemia, and limited evidence suggests that anidulafungin may be superior to fluconazole for candidemia and invasive candidiasis. The introduction of anidulafungin into clinical practice adds a third option for therapy in the echinocandin class. Research into its efficacy in other fungal infections is ongoing, and further studies into the impact of anidulafungin on economic outcomes will be beneficial.

Place in therapy:

Current evidence supports the use of anidulafungin in the management of candidemia, esophageal candidiasis, and invasive candidiasis, as demonstrated by the successful results in large multicenter clinical trials.     

Anidulafungin: a drug evaluation of a new echinocandin

Background: Over the past two decades, the frequency and type of invasive fungal infections have increased greatly and thus have driven the need for new antifungal agents. Anidulafungin is the newest addition to the echinocandin armamentarium. Objective: The intention of this review is to provide a drug evaluation of anidulafungin, including its spectrum of activity, pharmacokinetics, pharmacodynamics, clinical efficacy, adverse event profile, and its role in the treatment of invasive candidiasis. Methods: A PubMed search was performed to gather the most current and pertinent articles. Conclusions: Clinical trials have demonstrated anidulafungin's efficacy and tolerability in invasive candidiasis. Anidulafungin is not associated with any drug–drug interactions and does not require dosage adjustment in patients with renal and/or hepatic impairment.     

Newer systemic antifungal agents : pharmacokinetics, safety and efficacy

The past few years have seen the advent of several new antifungal agents, including those of a new class and a new generation of an existing class. Caspofungin, the first available echinocandin, has greatly expanded the antifungal armamentarium by providing a cell wall-active agent with candidacidal activity as well as demonstrated clinical efficacy in the therapy of aspergillosis refractory to available therapy. In addition, in clinical trials, caspofungin had comparable efficacy to amphotericin B for candidaemia and invasive Candida infections. Caspofungin and two more recently introduced echinocandins, micafungin and anidulafungin, are available as intravenous formulations only and characterised by potent anti-candidal activity, as well as few adverse events and drug interactions. Voriconazole, the first available second-generation triazole, available in both intravenous and oral formulations, has added a new and improved therapeutic option for primary therapy of invasive aspergillosis and salvage therapy for yeasts and other moulds. In a randomised trial, voriconazole demonstrated superior efficacy and a survival benefit compared with amphotericin B followed by other licensed antifungal therapy. This and data from a noncomparative study led to voriconazole becoming a new standard of therapy for invasive aspergillosis. Voriconazole has several important safety issues, including visual adverse events, hepatic enzyme elevation and skin reactions, as well as a number of drug interactions. Posaconazole, only available orally and requiring dose administration four times daily, shows encouraging efficacy in difficult to treat infections due to zygomycetes. Ravuconazole, available in both intravenous and oral formulations, has broad-spectrum in vitro potency and in vivo efficacy against a wide range of fungal pathogens. Clinical studies are underway. Despite the advances offered with each of these drugs, the morbidity and mortality associated with invasive fungal infections remains unacceptable, especially for the most at-risk patients. For individuals with severe immunosuppression as a result of chemotherapy, graft-versus-host disease and its therapy, or transplantation, new drugs and strategies are greatly needed.     

新型抗深部真菌感染药物——棘白霉素类

棘白霉素类(卡泊芬净、米卡芬净、阿尼芬净)抗真菌药是最新型的1种广谱抗真菌药,作用于真菌细胞壁,对于念珠菌属以及曲霉菌属均有效,使用安全性较高。该文主要综述了棘白霉素类药物的作用机制、适应证、抗菌谱、药动学、药物相互作用及不良反应。     

Echinocandins: A ray of hope in antifungal drug therapy

Invasive fungal infections are on the rise. Amphotericin B and azole antifungals have been the mainstay of antifungal therapy so far. The high incidence of infusion related toxicity and nephrotoxicity with amphotericin B and the emergence of fluconazole resistant strains of Candida glabrata egged on the search for alternatives. Echinocandins are a new class of antifungal drugs that act by inhibition of β (1, 3)-D- glucan synthase, a key enzyme necessary for integrity of the fungal cell wall.Caspofungin was the first drug in this class to be approved. It is indicated for esophageal candidiasis, candidemia, invasive candidiasis, empirical therapy in febrile neutropenia and invasive aspergillosis. Response rates are comparable to those of amphotericin B and fluconazole. Micafungin is presently approved for esophageal candidiasis, for prophylaxis of candida infections in patients undergoing hematopoietic stem cell transplant (HSCT) and in disseminated candidiasis and candidemia. The currently approved indications for anidulafungin are esophageal candidiasis, candidemia and invasive candidiasis.The incidence of infusion related adverse effects and nephrotoxicity is much lower than with amphotericin B. The main adverse effect is hepatotoxicity and derangement of serum transaminases. Liver function may need to be monitored. They are, however, safer in renal impairment. Even though a better pharmacoeconomical choice than amphotericin B, the higher cost of these drugs in comparison to azole antifungals is likely to limit their use to azole resistant cases of candidial infections and as salvage therapy in invasive aspergillosis rather than as first line drugs.     

Anidulafungin,a new antifungal drug

ObjectivesThe development of new antifungal drugs has become a challenge for pharmaceutical industry due to the increasing incidence of invasive fungal infections.MethodsExperience of existing antifungal drugs has shown that, like in bacteria against antibiotics, most fungal species, especially in Candida spp, resistance to previously active drugs is developing and constitutes a major problem in treating invasive fungal infections.ResultsAmong series of newer drugs, experimental data and literature search have unravelled a new class of antifungals, Echinocandins which inhibit successfully Candida spp resistant to other drugs such as fluconazole. One drug, anidulafungin has emerged recently in this class as one of the most active in invasive fungal infections.     

Anidulafungin (Eli Lilly & Co)

The pentyloxyterphenyl side chain derivative of echinocandin B, anidulafungin, is a 1,3-alpha-glucan synthesis inhibitor undergoing phase II clinical trials by Versicor and Eli Lilly, in various formulations, for the potential treatment of fungal and protozoal infections. Eli Lilly has retained options to the oral formulation of the compound, but development, clinical registration and marketing rights were licensed to Versicor in June 1999. The primary target of this compound is Candida, but Eli Lilly also intends to develop the drug for Aspergillus infections. No activity has been shown against Cryptococcus. The oral activity of anidulafungin is compromised by a low bioavailability, a decreased absorption when taken with food, and gastrointestinal side effects at higher doses. The development of a phosphorylated prodrug, LY-307853, which is converted in the body to anidulafungin by tissue and serum phosphatases, was discontinued in favor of an oral formulation, which uses anidulafungin directly. In February 1999, Deutsche Bank predicted sales of $100 million in 2001, rising to $300 million in 2003.     

Best practice guidelines for the management of adverse events associated with amphotericin B lipid complex

Importance of the field: Amphotericin B lipid complex is a widely used lipid-based formulation of amphotericin B, which has a broad spectrum of activity against a variety of fungal pathogens. It has also been shown to be significantly less nephrotoxic than conventional amphotericin B. However, infusional drug reactions, similar to those seen when using conventional amphotericin B, have been reported in a significant number of patients, so it is important that these are prevented or managed effectively, particularly in light of the changing epidemiology of systemic fungal infections.

Areas covered in this review: This article reviews effective strategies that can be used to reduce the risk of drug delivery reactions associated with amphotericin B lipid complex. Preserving renal function and managing spikes in serum creatinine levels are also discussed.

What the reader will gain: The aim of this paper is to provide healthcare professionals with clear guidance on the management of adverse events associated with amphotericin B lipid complex. Recommendations are based upon the published evidence and clinical experience from a number of different centres.

Take home message: Amphotericin B lipid complex represents a valuable therapeutic option in the treatment of fungal infections but improved strategies for the management of infusion-related adverse events are required.     

Anidulafungin: a new echinocandin for the treatment of fungal infections

Immunocompromised hosts are at increased risk for invasive fungal infections. Over the last five decades, the mainstay of therapy against systemic mycoses has revolved around amphotericin B deoxycholate. Unfortunately, this drug has substantial toxicities, and agents such as fluconazole were developed as an alternative to treat and prevent these invasive infections. Due to widespread use, fluconazole-resistant organisms have emerged; therefore, new agents with improved safety, efficacy and tolerability have now become desirable. The echinocandins are a new class of antifungal agents with novel activity against the fungal cell wall. In February 2006, the U.S. Food and Drug Administration approved the echinocandin anidulafungin for the treatment of patients with candidemia, peritonitis, intra-abdominal abscesses and esophageal candidiasis.     

In vitro interactions of anidulafungin with azole antifungals, amphotericin B and 5-fluorocytosine against Candida species

Anidulafungin, an echinocandin, is in late stage development for the treatment of fungal infections. We investigated the activity of anidulafungin in combination with other antifungal agents (fluconazole, itraconazole, ketoconazole, amphotericin B and 5-fluorocytosine) against four isolates each of Candida albicans, Candida glabrata, Candida parapsilosis and Candida tropicalis, and two isolates of Candida krusei using a macrobroth chequerboard method with interactions evaluated by fractional inhibitory concentration indices (FICIs). Additive activity (FICI > 0.5 to 1) or indifference (FICI > 1 to < 4) was observed in 85 of 90 interactions of anidulafungin with another antifungal agent. Synergy with itraconazole (FICIor=4), a drug rarely used systemically, was noted for four strains of C. tropicalis. The combination of anidulafungin and amphotericin B demonstrated additive activity for each of the 18 isolates of Candida tested. These results suggest additional studies are warranted, for example in animal models, to evaluate further the potential of combination antifungal therapy with anidulafungin for Candida infections.     

The echinocandins: three useful choices or three too many?

Echinocandins act by inhibiting 1,3-β-d-glucan synthesis in the fungal cell wall. The three licensed agents in this class, namely anidulafungin, caspofungin and micafungin, have a favourable pharmacological profile. These agents are narrow spectrum with clinically relevant activity against Candida and Aspergillus spp. Several trials have established the non-inferiority of these agents over existing agents in the treatment of invasive fungal infections. Caspofungin is also licensed for empirical antifungal therapy of presumed fungal infections in patients with febrile neutropenia. This paper reviews the literature on echinocandins.     

Echinocandin antifungal drugs in fungal infections: a comparison

This review compares the pharmacology, spectrum of antifungal activity, pharmacokinetic and pharmacodynamic properties, safety and clinical efficacy of the three licensed echinocandins: caspofungin, micafungin and anidulafungin. Echinocandins inhibit the synthesis of 1,3-β-D-glucan, an essential component of the fungal cell wall, and represent a valuable treatment option for fungal infections. The echinocandins exhibit potent in vitro and in vivo fungicidal activity against Candida species, including azole-resistant pathogens. For all agents, strains with drug minimum inhibitory concentrations (MICs) of ≤ 2?μg/mL are considered susceptible; the MIC at which 90% of isolates tested were inhibited (MIC??) values are typically <2?μg/mL but 100-fold higher MIC?? values are seen with Candida parapsilosis (1-2?μg/mL) and Candida guilliermondii (1-4?μg/mL). Activity is comparable between the three agents, although limited data indicate that anidulafungin may have low MICs against C. parapsilosis and Candida glabrata strains that demonstrate elevated MICs to caspofungin and micafungin. All three drugs have good fungistatic activity against Aspergillus spp., although minimal effective concentrations of micafungin and anidulfungin are 2- to 10-fold lower than those for caspofungin. Synergistic/additive in vitro effects of echinocandins when combined with a polyene or azole have been observed. Clinical resistance to the echinocandins is rare despite case reports of caspofungin resistance in several Candida spp. Resistance has been attributed to mutations in the FKS1 gene within two hot spot regions, leading to amino acid substitutions, mostly at position 645 (serine), yet not all FKS1 mutants have caspofungin MICs of >2?μg/mL. Of the three echinocandins, the in vitro 'paradoxical effect' (increased growth at supra-MIC drug concentrations) is observed least often with anidulafungin. All echinocandins have low oral bioavailability, and distribute well into tissues, but poorly into the CNS and eye. Anidulafungin is unique in that it undergoes elimination by chemical degradation in bile rather than via hepatic metabolism, has a lower maximum concentration and smaller steady state under the concentration-time curve but longer half-life than caspofungin or micafungin. In children, dosing should be based on body surface area. Daily doses of caspofungin (but not micafungin and anidulafungin) should be decreased (from 50 to 35?mg) in moderate liver insufficiency. All echinocandins display concentration-dependent fungicidal (for Candida) or fungistatic (for Aspergillus) activity. The postantifungal effect is 0.9-20 hours against Candida and <0.5 hours against Aspergillus. The echinocandins are well tolerated with few serious drug-drug interactions since they are not appreciable substrates, inhibitors or inducers of the cytochrome P450 or P-glycoprotein systems. In parallel with the greater clinical experience with caspofungin, this agent has a slightly higher potential for adverse effects/drug-drug interactions, with the least potential observed for anidulafungin. Caspofungin (but not micafungin or anidulafungin) dosing should be increased if coadministered with rifampicin and there are modest interactions of caspofungin with calcineurin inhibitors. All three agents are approved for the treatment of oesophageal candidiasis, candidaemia and other select forms of invasive candidiasis. Only micafungin is licensed for antifungal prophylaxis in stem cell transplantation, whereas caspofungin is approved for empirical therapy of febrile neutropenia. Caspofungin has been evaluated in the salvage and primary therapy of invasive aspergillosis. Combination regimens incorporating an echinocandin showing promise in the treatment of aspergillosis. However, echinocandins remain expensive to use.     

Anidulafungin and voriconazole in invasive fungal disease: pharmacological data and their use in combination

The incidence of invasive fungal infections has been increasing since the 1980s due to a growing population of immunocompromised and critically ill patients with associated risk factors including immunosuppressive chemotherapy, prolonged periods on intensive care units and infection with HIV. Persons who are severely immunocompromised are particularly vulnerable to infection from molds and yeasts that are often found naturally in the environment. In recent years, several new systemic antifungal agents have been released, significantly increasing options for the treatment of the most serious fungal infections. Newly available drugs as those in the echinocandin class include caspofungin, micafungin and anidulafungin, as well as the newer generation triazoles, voriconazole and posaconazole. In this review, the in vitro and in vivo activity of anidulafungin and voriconazole, both new antimycotic substances with a different mode of action, are analyzed.