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Antimicrobial Agents and Chemotherapy, September 2004, p. 3543-3551, Vol. 48, No. 9
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.9.3543-3551.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Disposition of Posaconazole following Single-Dose Oral Administration in Healthy Subjects

Philip Krieter,1 Brian Flannery,1 Timothy Musick,2 Mark Gohdes,2 Monika Martinho,1 and Rachel Courtney1*

Schering-Plough Research Institute, Kenilworth, New Jersey,1 Covance Laboratories, Madison, Wisconsin2

Received 5 November 2003/ Returned for modification 30 December 2003/ Accepted 2 April 2004

Posaconazole is a potent, broad-spectrum triazole antifungal agent currently in clinical development for the treatment of refractory invasive fungal infections. Eight healthy male subjects received a single 399-mg (81.7 µCi) oral dose of [14C]posaconazole after consuming a high-fat breakfast. Urine, feces, and blood samples were collected for up to 336 h postdose and assayed for total radioactivity; plasma and urine samples were also assayed for parent drug. Posaconazole was orally bioavailable, with a median maximum posaconazole concentration in plasma achieved by 10 h postdose. Thereafter, posaconazole was slowly eliminated, with a mean half-life of 20 h. The greatest peak in the radioactivity profile of pooled plasma extracts was due to posaconazole, with smaller peaks due to a monoglucuronide, a diglucuronide, and a smaller fragment of the molecule. The mean total amount of radioactivity recovered was 91.1%; the cumulative excretion of radioactivity in feces and in urine was 76.9 and 14.0% of the dose, respectively. Most of the fecal radioactivity was associated with posaconazole, which accounted for 66.3% of the administered dose; however, urine contained only trace amounts of unchanged posaconazole. The radioactivity profile of pooled urine extracts included two monoglucuronide conjugates and a diglucuronide conjugate of posaconazole. These observations suggest that oxidative (phase 1) metabolism by cytochrome P450 isoforms represents only a minor route of elimination for posaconazole, and therefore cytochrome P450-mediated drug interactions should have a limited potential to impact posaconazole pharmacokinetics.

* Corresponding author. Mailing address: Early Clinical Research and Experimental Medicine, Schering-Plough Research Institute, K-15-4-4455, 2015 Galloping Hill Rd., Kenilworth, NJ 07033. Phone: (908) 740-3836. Fax: (908) 740-2169. E-mail: rachel.courtney{at}spcorp.com.

Antimicrobial Agents and Chemotherapy, September 2004, p. 3543-3551, Vol. 48, No. 9
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.9.3543-3551.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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