Absorption; metabolism and excretion of a single oral dose of 14c-paliperidone 1mg in healthy subjects (PAL-053)

This study aimed to establish the absorption, metabolism and excretion of paliperidone. 5 male healthy subjects received a single oral dose 14C-paliperidone 1mg, among them 2 poor and 3 extensive metabolizers for cytochrome P450 2D6-mediated dextromethorphan O-demethylation. Drug and metabolite levels were analyzed using LC-MS/MS in urine, feces, blood and plasma collected pre-dose and up to 1 week post-dose. 1 week post-dose, 88.4–93.8% (mean 91.1%) of the radioactivity was excreted: 77.1–87.1% (mean 79.6%) in urine; 6.8–14.4% (mean 11.4%) in feces. ≤24h post-dose, unchanged drug (UD) accounted on average for 97% of the total radioactivity (TR) in plasma. Total body clearance of TR and UD averaged 97.9mL/min and 91.0mL/min, respectively. In urine, UD accounted for 51.4–67.5% (average 59.4%) of the dose administered, representing 65.5–82.1% (74.5%) of TR excreted into urine; similar percentages of parent drug were recovered in poor and extensive metabolizers. 4 urinary metabolites (R093725, R084852-glucuronide, monohydroxy-paliperidone, R125239) accounted for ≤6.5% of the dose; monohydroxy-paliperidone was only found in 2 extensive metabolizers. TR in feces was 11.4% of the dose; no fecal UD was found. 2 fecal metabolites (R084852 and monohydroxy-paliperidone) accounted for 0.4–0.9% of the dose. The low percentages of urinary and fecal metabolites indicate that paliperidone was metabolized to a limited extent. No important metabolic interactions are expected for paliperidone.

This study was supported by Supported from funding from Johnson & Johnson Pharmaceutical Services, LLC and Johnson & Johnson Pharmaceutical Research and Development.