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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...

Abstract. Prediction of human pharmacokinetics (PK) can be challenging for monoclonal antibodies (mAbs) exhibiting target-mediated drug disposition (TMDD). In this study, we performed a quantitative analysis of a diverse set of six mAbs exhibiting TMDD to explore translational rules that can be utilized to predict human PK. A TMDD model with rapid-binding approximation was utilized to fit PK and PD (i.e., free and/or total target levels) data, and average absolute fold error (AAFE) was calculated for each model parameter. Based on the comparative analysis, translational rules were developed and applied to a test antibody not included in the original analysis. AAFE of less than two-fold was observed between monkey and human for baseline target levels (R 0 ), body-weight (BW) normalized central elimination rate (K el /BW −0.25 ) and central volume (V c /BW 1.0 ). AAFE of less than three-fold was estimated for the binding affinity constant (K D ). The other four parameters, i.e., complex turnover rate (K int ), target turnover rate (K deg ), central to peripheral distribution rate constant (K pt ) and peripheral to central rate constant (K tp ) were poorly correlated between monkey and human. The projected human PK of test antibody based on the translation rules was in good agreement with the observed nonlinear PK. In conclusion, we recommend a TMDD model-based prediction approach that integrates in vitro human biomeasures and in vivo preclinical data using translation rules developed in this study.

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