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Antimicrobial Agents and Chemotherapy, February 2009, p. 703-707, Vol. 53, No. 2
0066-4804/09/$08.00+0     doi:10.1128/AAC.00663-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Intrapulmonary Pharmacokinetics and Pharmacodynamics of Posaconazole at Steady State in Healthy Subjects{triangledown}

John E. Conte Jr.,1,2,3* Jeffrey A. Golden,3 Gopal Krishna,4 Marina McIver,1,2 Emily Little,1,3 and Elisabeth Zurlinden1,3

American Health Sciences, San Francisco, California,1 Department of Epidemiology and Biostatistics,2 Department of Medicine, University of California—San Francisco, San Francisco, California,3 Schering-Plough Research Institute, Kenilworth, New Jersey4

Received 20 May 2008/ Returned for modification 28 September 2008/ Accepted 15 November 2008

We evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) of posaconazole (POS) in a prospective, open-label study. Twenty-five healthy adults received 14 doses of POS oral suspension (400 mg twice daily) with a high-fat meal over 8 days. Pulmonary epithelial lining fluid (ELF) and alveolar cell (AC) samples were obtained via bronchoalveolar lavage, and blood samples were collected during the 24 h after the last dose. POS concentrations were determined using liquid chromatography with tandem mass spectrometry parameters. The maximum concentrations (Cmax) (mean ± standard deviation) in plasma, ELF, and ACs were 2.08 ± 0.93, 1.86 ± 1.30, and 87.7 ± 65.0 µg/ml. The POS concentrations in plasma, ELF, and ACs did not decrease significantly, indicating slow elimination after multiple dosing. The mean concentrations of POS in plasma, ELF, and ACs were above the MIC90 (0.5 µg/ml) for Aspergillus spp. over the 12-h dosing interval and for 24 h following the last dose. Area under the curve from 0 to 12 h (AUC0-12) ratios for ELF/plasma and AC/plasma were 0.84 and 33. AUC0-24/MIC90 ratios in plasma, ELF, and AC were 87.6, 73.2, and 2,860. Nine (36%) of 25 subjects had treatment-related adverse events during the course of the study, which were all mild or moderate. We conclude that a dose of 400 mg twice daily resulted in sustained plasma, ELF, and AC concentrations above the MIC90 for Aspergillus spp. during the dosing interval. The intrapulmonary PK/PD of POS are favorable for treatment or prevention of aspergillosis, and oral POS was well tolerated in healthy adults.

* Corresponding author. Mailing address: Department of Medicine, University of California at San Francisco, 350 Parnassus Avenue, Suite 305, San Francisco, CA 94117. Phone: (415) 924-2470. Fax: (415) 731-4760. E-mail: john.conte{at}ucsf.edu

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

Antimicrobial Agents and Chemotherapy, February 2009, p. 703-707, Vol. 53, No. 2
0066-4804/09/$08.00+0     doi:10.1128/AAC.00663-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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