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Antimicrob. Agents Chemother. doi:10.1128/AAC.00663-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

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

American Health Sciences, San Francisco, California; Department of Epidemiology & Biostatistics, Department of Medicine, University of California—San Francisco, San Francisco, California; Schering-Plough Research Institute, Kenilworth, New Jersey

^* To whom correspondence should be addressed. Email: John.conte{at}ucsf.edu.

	Abstract

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 (C_max) (mean ± SD) in plasma, ELF, and AC were 2.08 ± 0.93, 1.86 ± 1.30, and 87.7 ± 65.0 µg/ml. POS concentrations in plasma, ELF, and AC did not decrease significantly, indicating slow elimination after multiple dosing. Mean concentrations of POS in plasma, ELF, and AC were above the MIC₉₀ (0.5 µg/ml) for Aspergillus species over the 12-h dosing interval and for 24 hours following the last dose. Area under the curve (AUC_0-12h) ratios for ELF/plasma and AC/plasma were 0.84 and 33. AUC_0-24h/MIC₉₀ ratios in plasma, ELF, and AC were 87.6, 73.2, and 2860. 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 BID resulted in sustained plasma, ELF, and AC concentrations above the MIC₉₀ for Aspergillus spp. during the dosing interval. The intrapulmonary PK/PD of POS is favorable for treatment or prevention of aspergillosis, and oral POS was well tolerated in healthy adults.