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Antimicrobial Agents and Chemotherapy, October 2004, p. 3823-3827, Vol. 48, No. 10
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.10.3823-3827.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Intrapulmonary Pharmacokinetics and Pharmacodynamics of Itraconazole and 14-Hydroxyitraconazole at Steady State

John E. Conte Jr.,1,2,3* Jeffrey A. Golden,2 Juliana Kipps,1 Marina McIver,1 and Elisabeth Zurlinden1

Infectious Diseases Research Group, Department of Epidemiology & Biostatistics,1 Department of Medicine,2 Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, California3

Received 30 January 2004/ Returned for modification 1 March 2004/ Accepted 15 June 2004

We determined the steady-state intrapulmonary pharmacokinetic and pharmacodynamic parameters of orally administered itraconazole (ITRA), 200 mg every 12 h (twice a day [b.i.d.]), on an empty stomach, for a total of 10 doses, in 26 healthy volunteers. Five subgroups each underwent standardized bronchoscopy and bronchoalveolar lavage (BAL) at 4, 8, 12, 16, and 24 h after administration of the last dose. ITRA and its main metabolite, 14-hydroxyitraconazole (OH-IT), were measured in plasma, BAL fluid, and alveolar cells (AC) using high-pressure liquid chromatography. Half-life and area under the concentration-time curves (AUC) in plasma, epithelial lining fluid (ELF), and AC were derived using noncompartmental analysis. ITRA and OH-IT maximum concentrations of drug (Cmax) (mean ± standard deviation) in plasma, ELF, and AC were 2.1 ± 0.8 and 3.3 ± 1.0, 0.5 ± 0.7 and 1.0 ± 0.9, and 5.5 ± 2.9 and 6.6 ± 3.1 µg/ml, respectively. The ITRA and OH-IT AUC for plasma, ELF, and AC were 34.4 and 60.2, 7.4 and 18.9, and 101 and 134 µg · hr/ml. The ratio of the Cmax and the MIC at which 90% of the isolates were inhibited (MIC90), the AUC/MIC90 ratio, and the percent dosing interval above MIC90 for ITRA and OH-IT concentrations in AC were 1.1 and 3.2, 51 and 67, and 100 and 100%, respectively. Plasma, ELF, and AC concentrations of ITRA and OH-IT declined monoexponentially with half-lives of 23.1 and 37.2, 33.2 and 48.3, and 15.7 and 45.6 h, respectively. An oral dosing regimen of ITRA at 200 mg b.i.d. results in concentrations of ITRA and OH-ITRA in AC that are significantly greater than those in plasma or ELF and intrapulmonary pharmacodynamics that are favorable for the treatment of fungal respiratory infection.

* Corresponding author. Mailing address: University of California, San Francisco, 350 Parnassus Ave., Suite 507, San Francisco, CA 94117. Phone: (415) 476-1312. Fax: (415) 476-0760. E-mail: 1jconte99{at}comcast.net.

Antimicrobial Agents and Chemotherapy, October 2004, p. 3823-3827, Vol. 48, No. 10
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.10.3823-3827.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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