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 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.

FIG. 1.

Structure of [¹⁴C]posaconazole. The asterisk indicates the position of the ¹⁴C label.

FIG. 2.

Mean posaconazole- and drug-derived radioactivity concentration in plasma-time profiles after a single oral dose of 399 mg of [¹⁴C]posaconazole given to eight healthy male subjects.

FIG. 3.

Mean cumulative percentage of radioactive dose in feces, urine, and fecal wipes after a single oral dose of 399 mg of [¹⁴C]posaconazole given to eight healthy male subjects.

FIG. 4.

Radioactivity profile of pooled plasma extracts at 5, 12, and 24 h after a single oral dose of 399 mg of [¹⁴C]posaconazole given to eight healthy male subjects.

FIG. 5.

Radioactivity profile of a pooled (0 to 120 h) urine extract after a single oral dose of 399 mg of [¹⁴C]posaconazole given to eight healthy male subjects.

FIG. 6.

Radioactivity profile of a pooled (0 to 120 h) fecal extract (top) and expanded view (bottom) after a single oral dose of 399 mg of [¹⁴C]posaconazole given to eight healthy male subjects.

FIG. 7.

Proposed metabolic pathway of [¹⁴C]posaconazole in healthy male subjects.

FIG. 8.

Representative mass spectra of posaconazole and glucuronide conjugates. (A) Posaconazole in pooled plasma collected 24 h postdose; (B) metabolite M8 in 0- to 120-h pooled urine; (C) metabolite M9 in 0- to 120-h pooled urine; (D) metabolite M5 in 0- to 120-h pooled urine from subject 2.