Steady-state disposition of the nonpeptidic protease inhibitor tipranavir when coadministered with ritonavir

Abstract

The pharmacokinetic and metabolite profiles of the antiretroviral agent tipranavir (TPV), administered with ritonavir (RTV), in nine healthy male volunteers were characterized. Subjects received 500-mg TPV capsules with 200-mg RTV capsules twice daily for 6 days. They then received a single oral dose of 551 mg of TPV containing 90 microCi of [(14)C]TPV with 200 mg of RTV on day 7, followed by twice-daily doses of unlabeled 500-mg TPV with 200 mg of RTV for up to 20 days. Blood, urine, and feces were collected for mass balance and metabolite profiling. Metabolite profiling and identification was performed using a flow scintillation analyzer in conjunction with liquid chromatography-tandem mass spectrometry. The median recovery of radioactivity was 87.1%, with 82.3% of the total recovered radioactivity excreted in the feces and less than 5% recovered from urine. Most radioactivity was excreted within 24 to 96 h after the dose of [(14)C]TPV. Radioactivity in blood was associated primarily with plasma rather than red blood cells. Unchanged TPV accounted for 98.4 to 99.7% of plasma radioactivity. Similarly, the most common form of radioactivity excreted in feces was unchanged TPV, accounting for a mean of 79.9% of fecal radioactivity. The most abundant metabolite in feces was a hydroxyl metabolite, H-1, which accounted for 4.9% of fecal radioactivity. TPV glucuronide metabolite H-3 was the most abundant of the drug-related components in urine, corresponding to 11% of urine radioactivity. In conclusion, after the coadministration of TPV and RTV, unchanged TPV represented the primary form of circulating and excreted TPV and the primary extraction route was via the feces.

FIG. 1.

Structure of the sulfonamide-substituted dihydropyrone PI TPV. The asterisk denotes the ¹⁴C label.

FIG. 2.

Radioactivity in plasma (○) and blood (•) after a single oral dose of [¹⁴C]TPV administered during the steady state. Means ± SDs are shown (n = 9). (Inset) Cumulative excretion of radioactivity in urine (□) and feces (○) and total radioactivity (•). Means ± SDs are shown (n = 8).

FIG. 3.

Steady-state concentrations of TPV in plasma (Cp). Solid line, geometric mean; dashed line, median; day 1 to day 6, evening trough concentrations; day 7, morning and evening trough concentrations (evening concentrations were not normalized to the TPV dose of approximately 551 mg per subject); day 8 to day 15, morning trough concentrations (n = 7).

FIG. 4.

Representative radiochromatograms for the 3-h plasma sample pooled from all nine subjects (a) and the urine (b) and feces (c) samples from subject 106 after the administration of the [¹⁴C]TPV dose.

FIG. 5.

Comparison of MS-MS results for the TPV standard (a) and metabolites H-1 (b) and H-2 (c).

FIG. 6.

Proposed metabolic pathways of TPV administered with RTV. Gluc, glucuronide.