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 Ci 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.

Metabolism-Mediated Drug Interactions Associated with Ritonavir-Boosted Tipranavir in Mice

“…Metabolites were identified using a flow scintillation analyzer in conjunction with liquid chromatography-tandem mass spectrometry. The most abundant metabolite in feces was identified as an oxidation metabolite, whereas a TPV glucuronide metabolite was identified in urine (Chen et al, 2007b). In these two studies, two monohydroxylation metabolites, a dehydrogenation metabolite, and a glucuronide conjugate metabolite of TPV were observed (Chen et al, 2007b;Macha et al, 2007).…”

“…This finding is in accordance with previous studies using radiolabeled TPV. In previous studies, two monohydroxylated metabolites, one dehydrogenated metabolite, and one glucuronide-conjugated metabolite have been reported (Chen et al, 2007b;Macha et al, 2007). In these reports, one hydroxylation took place in a benzyl group, and the other hydroxylation occurred in a trifluoromethyl-substituted pyridinyl ring.…”

“…The most abundant metabolite in feces was identified as an oxidation metabolite, whereas a TPV glucuronide metabolite was identified in urine (Chen et al, 2007b). In these two studies, two monohydroxylation metabolites, a dehydrogenation metabolite, and a glucuronide conjugate metabolite of TPV were observed (Chen et al, 2007b;Macha et al, 2007). However, neither the contributions of P450s in TPV metabolism nor the effects of RTV on TPV metabolism are clear.…”

Tipranavir: a novel protease inhibitor for HIV therapy

“…TPV is more than 99.9% bound to serum albumin and α-1-acid glycoproteins. Due to the inhibition of metabolism by RTV, TPV is eliminated mostly unchanged through biliary excretion, with minor urinary excretion [16].…”

Pharmacologic characteristics of investigational and recently approved agents for the treatment of HIV

“…Tipranavir is highly bound to plasma proteins (>99.9%) [97]. Seventy-five and 24% of a radiolabeled dose of tipranavir are recovered in the feces and urine, respectively [98]. The effects of tipranavir/ritonavir on CYP enzymes and P-gp are complex, and differ at first dose versus steady state.…”