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Antimicrobial Agents and Chemotherapy, March 2009, p. 1149-1156, Vol. 53, No. 3
0066-4804/09/$08.00+0     doi:10.1128/AAC.01279-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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

Bharat D. Damle,1 James A. Dowell,2 Robert L. Walsky,3 Gregory L. Weber,4 Martin Stogniew,2 and Philip B. Inskeep3*

Pfizer Inc., New York, New York,1 Vicuron Pharmaceuticals, Subsidiary of Pfizer Inc., New York, New York,2 Pfizer Inc., Groton, Connecticut,3 Pfizer Inc., St. Louis, Missouri4

Received 23 September 2008/ Returned for modification 1 November 2008/ Accepted 15 November 2008

Anidulafungin is a novel semisynthetic echinocandin with potent activity against Candida (including azole-resistant 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.

* Corresponding author. Mailing address: Pharmacokinetics, Dynamics, and Metabolism, Pfizer Global Research and Development, MS 8118D-2012, Groton, CT 06340. Phone: (860) 441-3305. Fax: (860) 715-8082. E-mail: philip.b.inskeep{at}pfizer.com

{triangledown} Published ahead of print on 24 November 2008.

Antimicrobial Agents and Chemotherapy, March 2009, p. 1149-1156, Vol. 53, No. 3
0066-4804/09/$08.00+0     doi:10.1128/AAC.01279-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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