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

Abstract

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...

Tissue Penetration of Antifungal Agents

“…In contrast, micafungin concentrations in rat kidneys exceed those in plasma 5 min after dosing, by 1.6-fold, but then decline in parallel with plasma concentrations (150). All three echinocandins exhibit low concentrations (Ͻ2% of the dose) (104,181,182) of unchanged drug in human urine. There are reported cases of the efficacy of the echinocandins in patients with candiduria (183,184), but this may reflect the attainment of high concentrations in renal parenchyma.…”

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

“…[15][16][17] This pathway is a main mechanism of clearance in vivo for each of these therapeutics. 14 In great contrast, CD101 is highly stable in plasma from various species and in PBS buffer. As illustrated in Figure 3, the ring-opening step that initiates the chemical degradation cascade of anidulafungin and other echinocandins is disfavored in CD101 because of the presence of the hemiaminal ether moiety.…”

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

“…109 Elimination of anidulafungin is via bile in the faeces, with o10% of the drug excreted unchanged in the faeces and o1% in urine. 107,110 Genetic variation of CYP or phase II enzymes or the hepatic transporters is unlikely to affect anidulafungin pharmacokinetics, given their lack of interaction with anidulafungin, and hence pharmacogenomic analysis will not inform clinical use.…”