The Echinocandins: Comparison of Their Pharmacokinetics, Pharmacodynamics and Clinical Applications

Abstract

Caspofungin, micafungin and anidulafungin are three drugs of the echinocandin class of antifungals available for intravenous treatment of invasive candidiasis and aspergillosis. They exhibit high in vitro and in vivo activities against Candida spp. and Aspergillus spp. In various clinical studies investigating candidemia and invasive candidiasis, Candida esophagitis, and fever in neutropenia, the clinical efficacy of the echinocandin tested was similar to that of established antifungals. Antifungal activity against strains no longer susceptible to conventional antifungal agents, such as fluconazole and amphotericin B suggests that echinocandins can be used as salvage therapy in life-threatening fungal infections. There is no cross-resistance to other antifungals. Excellent safety and tolerability of treatment with caspofungin has been documented over a total of 4.3 million patient days. Echinocandins are poor substrates of the cytochrome P450 enzyme family and can be safely co-administered with most drugs without the need for dosage adaptation. No dose reduction is required in renal impairment. A reduction in the daily maintenance dose has been recommended for caspofungin, but not for micafungin and anidulafungin in patients presenting with mild to moderate hepatic failure.

CD101, a novel echinocandin with exceptional stability properties and enhanced aqueous solubility

“…We used anidulafungin as the comparator in these studies not only because of the structural similarity to CD101, but also because anidulafungin has the longest plasma half-life of the approved echinocandins across species. [18][19][20][21][22] The unique chemical stability of CD101 has largely circumvented the main route of elimination (chemical degradation via ring opening) that is observed for anidulafungin and is likely a key contributor to the improved pharmacokinetics of CD101, although this alone may not entirely explain the long half-life that is observed in vivo across species (typically 3-fold to 5-fold longer than that of anidulafungin). 10 In addition, the lack of degradation and the absence of open-chain aldehyde formation suggest that CD101 may offer higher margins of safety with fewer dose-limiting toxicities over echinocandins that generate such reactive degradants.…”

Has the era of individualised medicine arrived for antifungals? A review of antifungal pharmacogenomics

“…97 An initial open-ring metabolite is found in plasma, with subsequent peptide degradation resulting in low MW products found in urine. Within 4 weeks, 41% of the dose is excreted in urine and 35% in faeces 98 as metabolites.…”

“…107 Anidulafungin is extensively bound by plasma proteins 108 and undergoes biotransformation, rather than metabolism, undergoing a slow, nonenzymatic degradation to inactive peptides. 97 Neither phase 1 nor phase 2 hepatic metabolism is involved in elimination of anidulafungin, nor is it a substrate, inducer or inhibitor of CYP450. At physiologically relevant concentrations it does not inhibit OATP.…”

Management of invasive candidiasis and candidemia in adult non-neutropenic intensive care unit patients: Part II. Treatment

“…The potential limitations of high drug doses include a paradoxical decrease in microbial kill (the eagle effect) as well as the toxicity of high intermittent doses [41]. Finally the main difference between caspofungin, micafungin, and anidulafungin relates on the elimination profile, the half life and the distribution volume [42]. Additional pharmacokinetics studies are needed in ICU patients [43].…”