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Antimicrobial Agents and Chemotherapy, December 2009, p. 5102-5107, Vol. 53, No. 12
0066-4804/09/$08.00+0     doi:10.1128/AAC.01042-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Bronchopulmonary Disposition of Intravenous Voriconazole and Anidulafungin Given in Combination to Healthy Adults{triangledown}

Jared L. Crandon,1 Mary Anne Banevicius,1 Annie F. Fang,2 Penelope H. Crownover,2 R. Fredrick Knauft,3 J. Samuel Pope,3 John H. Russomanno,3 Eric Shore,3 David P. Nicolau,1,4 and Joseph L. Kuti1*

Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut,1 Pfizer Inc., New York, New York,2 Department of Medicine, Division of Pulmonology,3 Division of Infectious Diseases, Hartford Hospital, Hartford, Connecticut4

Received 24 July 2009/ Returned for modification 23 August 2009/ Accepted 9 September 2009

Voriconazole and anidulafungin in combination are being investigated for use for the treatment of pulmonary aspergillosis. We determined the pulmonary disposition of these agents. Twenty healthy participants received intravenous voriconazole (at 6 mg/kg of body weight every 12 h [q12h] on day 1 and then at 4 mg/kg q12h) and anidulafungin (200 mg on day 1 and then 100 mg every 24 h) for 3 days. Five participants each were randomized for collection of bronchoalveolar lavage samples at times of 4, 8, 12, and 24 h. Drug penetration was determined by the ratio of the total drug area under the concentration-time curve during the dosing interval (AUC0-{tau}) for epithelial lining fluid (ELF) and alveolar macrophages (AM) to the total drug AUC0-{tau} in plasma. The mean (standard deviation) half-life and AUC0-{tau} were 6.9 (2.1) h and 39.5 (19.8) µg·h/ml, respectively, for voriconazole and 20.8 (3.1) h and 101 (21.8) µg·h/ml, respectively, for anidulafungin. The AUC0-{tau} values for ELF and AM were 282 and 178 µg·h/ml, respectively, for voriconazole, and 21.9 and 1,430 µg·h/ml, respectively, for anidulafungin. This resulted in penetration ratios into ELF and AM of 7.1 and 4.5, respectively, for voriconazole and 0.22 and 14.2, respectively, for anidulafungin. The mean total concentrations of both drugs in ELF and AM at 4, 8, 12, and 24 h remained above the MIC90/90% minimum effective concentration for most Aspergillus species. In healthy adult volunteers, voriconazole achieved high levels of exposure in both ELF and AM, while anidulafungin predominantly concentrated in AM.

* Corresponding author. Mailing address: Center for Anti-Infective Research and Development, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102. Phone: (860) 545-3612. Fax: (860) 545-3992. E-mail: jkuti{at}harthosp.org

{triangledown} Published ahead of print on 21 September 2009.

Antimicrobial Agents and Chemotherapy, December 2009, p. 5102-5107, Vol. 53, No. 12
0066-4804/09/$08.00+0     doi:10.1128/AAC.01042-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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