In vitro activity of voriconazole, itraconazole, caspofungin, anidulafungin (VER002, LY303366) and amphotericin B against aspergillus spp

Serrano, M. C. López; Valverde-Conde, Anastasio; Diego, María José Chávez de; Bernal, Samuel; Claro, R.; Pemán, Javier; Ramírez, M.; Martín-Mazuelos, Estrella

doi:10.1016/s0732-8893(02)00507-2

Cited by 71 publications

(9 citation statements)

References 32 publications

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“…Members of this class include caspofungin, micafungin, and anidulafungin; the latter is a novel semisynthetic echinocandin with potent in vitro and in vivo activities against Candida spp. and Aspergillus spp., the major causes of deep-seated mycoses (4,5,24). Anidulafungin is approved in the United States and Europe for the treatment of candidemia in nonneutropenic patients and other forms of invasive Candida infections (11,25).…”

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confidence: 99%

In Vitro and In Vivo Studies To Characterize the Clearance Mechanism and Potential Cytochrome P450 Interactions of Anidulafungin

Damle

Dowell

Walsky

et al. 2009

Antimicrob Agents Chemother

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Anidulafungin is a novel semisynthetic echinocandin with potent activity against Candida (including azoleresistant isolates) and Aspergillus spp. and is used for serious systemic fungal infections. The purpose of these studies was to characterize the clearance mechanism and potential for drug interactions of anidulafungin. Experiments included in vitro degradation of anidulafungin in buffer and human plasma, a bioassay for antifungal activity, in vitro human cytochrome P450 inhibition studies, in vitro incubation with rat and human hepatocytes, and mass balance studies in rats and humans. Clearance of anidulafungin appeared to be primarily due to slow chemical degradation, with no evidence of hepatic-mediated metabolism (phase 1 or 2). Under physiological conditions, further degradation of the primary degradant appears to take place. The primary degradation product does not retain antifungal activity. Anidulafungin was not an inhibitor of cytochrome P450 enzymes commonly involved in drug metabolism. Mass balance studies showed that anidulafungin was eliminated in the feces predominantly as degradation products, with only a small fraction (10%) eliminated as unchanged drug; fecal elimination likely occurred via biliary excretion. Only negligible renal involvement in the drug's elimination was observed. In conclusion, the primary biotransformation of anidulafungin is mediated by slow chemical degradation, with no evidence for hepatic enzymatic metabolism or renal elimination.The echinocandins are a relatively new class of parenterally administered antifungal agents that have been developed for the treatment of serious systemic fungal infections. Members of this class include caspofungin, micafungin, and anidulafungin; the latter is a novel semisynthetic echinocandin with potent in vitro and in vivo activities against Candida spp. and Aspergillus spp., the major causes of deep-seated mycoses (4,5,24). Anidulafungin is approved in the United States and Europe for the treatment of candidemia in nonneutropenic patients and other forms of invasive Candida infections (11,25). Anidulafungin ( Fig. 1) has distinct pharmacokinetic characteristics, activity against azole-resistant Candida spp., and a favorable safety profile, all of which support its use for systemic fungal infections (26).Echinocandins mediate their antifungal activity by noncompetitive inhibition of (1,3)-␤-D-glucan synthase, a fungus-specific enzyme essential for the synthesis of cell wall glucan (5). While this mode of action is common to all members of the class, there appear to be some differences among echinocandins with respect to their pharmacokinetic properties, including drug disposition (3,5,26). Some of these differences may have implications for the concomitant use of these agents with other drugs and for their use in special patient populations, particularly those under intensive care.To this end, the studies described here were designed to characterize the clearance mechanism and disposition of anidulafungin in rats and humans, as well as to...

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confidence: 99%

In Vitro and In Vivo Studies To Characterize the Clearance Mechanism and Potential Cytochrome P450 Interactions of Anidulafungin

Damle

Dowell

Walsky

et al. 2009

Antimicrob Agents Chemother

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“…Echinocandins prevent fungal cell wall synthesis through noncompetitive inhibition of (1,3)‐β‐D‐glucan synthase, an enzyme specific to fungi that is essential for cell wall formation 1 . Studies in vitro show that at clinically achievable concentrations, anidulafungin possesses potent antifungal activity against Candida spp, including strains resistant to azoles and polyenes, and Aspergillus spp 1–3 . These pathogens are a major cause of systemic fungal infections in immunocompromised patients, such as those with neutropenic cancer or HIV/AIDS, 4,5 as well as in patients receiving immunosuppressant therapy following solid organ transplantation 6 …”

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confidence: 99%

Anidulafungin Does Not Require Dosage Adjustment in Subjects With Varying Degrees of Hepatic or Renal Impairment

Dowell

Stogniew

Krause

et al. 2007

The Journal of Clinical Pharma

106

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Two open-label studies assessed the effects of hepatic and renal impairment on anidulafungin pharmacokinetics. A single 50-mg dose was administered intravenously to subjects with varying degrees of hepatic or renal insufficiency or with end-stage renal disease; all were matched to normal healthy controls. Anidulafungin was well tolerated. AUC, CL, C(max), t(max), t(1/2), and V(ss) between renally impaired subjects and controls were not significantly different (P>.05), and no measurable amounts of drug were found in dialysate. The same pharmacokinetic parameters were also not affected (P>.05) by mild or moderate hepatic insufficiency, with respective mean AUCs of 50.6 +/- 11.7 microg x h/mL and 68.6 +/- 14.5 microg x h/mL, compared to 70.0 +/- 13.4 microg x h/mL in controls. Statistically significant decreases (P<05) of AUC (33% change) and C(max) (36% change) in severely hepatically impaired subjects compared to controls--most likely secondary to ascites and edema--were not clinically relevant. Anidulafungin can be safely administered to patients with any degree of hepatic or renal impairment without dosage adjustment and without regard to hemodialysis schedules.

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“…The echinocandins are active against Aspergillus spp 16–20. The MIC 90 for anidulfungin against A. fumigatus is ≤0.25 μg/mL 16,17. Activity against other species of Aspergillus is similar to that seen against fumigatus.…”

Section: Spectrum Of Activitymentioning

confidence: 92%

Anidulafungin and its role in candida infections

Cappelletty

Jung²

2009

IDR

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Candida infections continue to play a significant role not only in critically ill and immunocompromised patients but also in non-compromised patients. The incidence of systemic fungal infections in the United States has been on the rise for the past 30 years. Anidulafungin and all echinocandins inhibit glucan synthase thus inhibiting the formation of 1,3-β-D-glucan which is an essential component of the fungal cell wall. The decrease in 1,3-β-D-glucan results in the osmotic lysis of the cell, resulting in fungicidal activity against candida. Anidulafungin is active against most species of candida and resistance to it is very rare. Two potential mechanisms conferring reduced susceptibility to the echinocandins are efflux and target alteration. The efflux pump associated with fluconazole resistance in Candida albicans can confer higher minimum inhibitory concentrations to caspofungin. The second mechanism of resistance is via mutations in the genes which code for 1,3 β-D-glucan synthase, specifically FKS1. Because of its spectrum of activity, fungicidal nature, and tolerability it is an attractive first-line therapeutic choice for treating candidemia in both non-neutropenic and neutropenic patients. Because it is available only parenterally its role in treating mucocutaneous candidiasis is primarily in patients unable to take oral therapy.

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In vitro activity of voriconazole, itraconazole, caspofungin, anidulafungin (VER002, LY303366) and amphotericin B against aspergillus spp

Cited by 71 publications

References 32 publications

In Vitro and In Vivo Studies To Characterize the Clearance Mechanism and Potential Cytochrome P450 Interactions of Anidulafungin

In Vitro and In Vivo Studies To Characterize the Clearance Mechanism and Potential Cytochrome P450 Interactions of Anidulafungin

Anidulafungin Does Not Require Dosage Adjustment in Subjects With Varying Degrees of Hepatic or Renal Impairment

Anidulafungin and its role in candida infections

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