Disposition of posaconazole following single-dose oral administration in healthy subjects.
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 microCi) oral dose of [(14)C]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.
Early Clinical Research and Experimental Medicine, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA.
Philip
P
Krieter
Brian
B
Flannery
Timothy
T
Musick
Mark
M
Gohdes
Monika
M
Martinho
Rachel
R
Courtney
D000328:Adult; D000935:Antifungal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D005243:Feces / Q000737:chemistry; D020719:Glucuronides / Q000378:metabolism; D006801:Humans; D007408:Intestinal Absorption; D008297:Male; D013058:Mass Spectrometry; D013056:Spectrophotometry, Ultraviolet; D013535:Suspensions; D014230:Triazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*
D000935:Antifungal Agents; D020719:Glucuronides; D013535:Suspensions; D014230:Triazoles; C101425:posaconazole