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

Abstract

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 Ci) 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.Posaconazole (SCH 56592) is a potent, extended-spectrum triazole antifungal agent currently in late-phase clinical development for the treatment and prophylaxis of invasive fungal infections due to a wide range of common, rare, and emerging molds and yeasts. Posaconazole has demonstrated in vitro activity against several commonly encountered pathogens, including Candida, Aspergillus, Cryptococcus, and Coccidioides species (1,7,12,13). In addition, its activity against several emerging pathogens, such as the filamentous fungus Scedosporium (3, 10), has been explored clinically. In an immunocompromised patient, posaconazole has been used to effectively treat Scedosporium-induced brain abscesses that were refractory to itraconazole and amphotericin B therapy (11).The anticipated clinical dosage regimen of posaconazole oral suspension for the treatment of refractory invasive fungal infections is 400 mg twice daily. The purpose of the present study was to determine the absorption, metabolism, and excretion of a single 400-mg dose of [ 14 C]posaconazole oral suspension in human subjects. MATERIALS AND METHODS Radiolabeled posaconazole and dosage forms. [14 C]posaconazole ( Fig. 1) was synthesized and formulated by the radiochemistry group at the Schering-Plough Research Institute (Kenilworth, N.J.). Its specific activity was 0.205 Ci/mg, and its radiochemical purity was 98.7%. The radiolabeled drug was ...

A routine method for the quantification of the novel antimycotic drug posaconazole in plasma using liquid chromatography-tandem mass spectrometry

“…Several HPLC methods for the quantitation of posaconazole in human plasma employing ultraviolet detection have been described previously (14)(15)(16). These methods require laborious sample preparation along with extensive chromatographic run times.…”

“…Three mass spectrometric methods for the quantification of posaconazole in human plasma have been published previously (16)(17)(18). Some of these methods are laborious, employing solvent extraction with an evaporation step (18).…”

Has the era of individualised medicine arrived for antifungals? A review of antifungal pharmacogenomics

“…Posaconazole is excreted largely unchanged; there are no active metabolites 88 and the metabolites seen in urine are glucuronide conjugates, 89 produced by UGT1A4. 90 Genetic variants occur in the alleles for this enzyme, 91 some of which cause reduced catalytic activity.…”

Farmacología de los azoles

“…Todos los azoles tienen un volumen de distribución muy elevado que supera, con creces, el contenido de agua corporal que señala de forma clara la afinidad tisular de estos fármacos, y justifica la escasa presencia en plasma [8,14,17,31]. Voriconazol, de forma característica, y que probablemente comparte con los restantes azoles, alcanza una concentración intracelular elevada en polimorfonucleares humanos con una penetración rápida, no saturable e independiente de las condiciones ambientales [5].…”

“…Además, la implicación de este complejo sistema enzimático obliga a valorar la posibilidad de que se produzcan interacciones con potencial riesgo, sustentadas en este caso, en la inhibición de las isoenzimas que participan en su metabolismo. Itraconazol, voriconazol [17] …”