A Study of Plasma Concentrations, Metabolism and Excretion of 14C-paliperidone After a Single Oral Dose

Overview

The purposes of this study are to investigate the metabolic pathways of paliperidone and excretion of paliperidone and its metabolites in healthy adult male volunteers, both CYP2D6 poor and extensive metabolizers, after administration of a single 1-mg oral dose of 14C-paliperidone, to evaluate the safety and tolerability of paliperidone, and to determine the relationship between genotypes (CYP2D6, CYP3A4, CYP3A5, UGT1A1, and UGT1A6) and exposure to paliperidone and its metabolites.

This study is designed as a single-center, single-dose, open-label study of the absorption, metabolism, and excretion of paliperidone in healthy men (3 extensive and 3 poor metabolizers based on CYP2D6 phenotype). Eligible volunteers will be admitted to the study center the evening before study drug administration and will remain at the study center until 168 hours after dosing (or longer if required up to a maximum of 14 days). Each volunteer will receive a single oral dose of 14C-paliperidone with total radioactivity below 1000 µSv (16 mCi). Blood samples for plasma pharmacokinetic profile will be obtained immediately before study drug administration and 0.5, 1, 1.5, 3, 6, 12, 16, 36, 48, 72, 96, 120, 144 and 168 hours postdose. Blood samples will be obtained 2, 4, 8 and 24 hours postdose for determination of 14C in whole blood. Samples for determination of serum creatinine will be obtained 2, 4, 8 and 24 hours postdose. Urine will be collected immediately prior to drug administration and from 0-4, 4-8, 8-12, 12-16, 16-24, 24-36, 36-48, 48-72, 72-96, 96-120, 120-144, and 144-168 hours after study drug administration. Fecal samples will be collected per each stool, once before study drug administration and in the period from 0-168 hours after study drug administration. Collections of urine and feces (per 24 hours) will continue beyond 168 hours, to a maximum of 336 hours (Day 15) for patients who excrete radioactivity slowly (2 latest 24-hour urine collections each greater than or equal to 2% of total radioactive dose) or have \<7 feces stool samples over the 0 to 168-hour period. 14C radioactivity will be measured in plasma, urine, and feces. Aliquots of the 0- through 24 hour urine collections will be analyzed for creatinine. Plasma concentrations of paliperidone and risperidone will be determined by means of a validated LC MS/MS method. The 14C-labeled moiety in plasma and urine will be determined by liquid scintillation counting. For all plasma samples, the lower limits of quantification for paliperidone and risperidone will be 0.100 ng/mL. For all plasma and urine samples the lower limits of quantification for 14C-paliperidone will be 72 dpm/mL (=2.0n g eq/mL). The rationale for the present study with a single-dose administration of 1 mg 14C-paliperidone to healthy white men is to determine the routes of excretion for paliperidone and to elucidate the metabolic pathways and structures of predominant paliperidone metabolites. As such, this study will result in a more complete understanding of the pharmacokinetics of paliperidone in humans. Safety and tolerability will be monitored. Volunteers will receive a single oral 1 mg dose of 14C-paliperidone as a solution with a specific activity of 592 kBq/mg, resulting in an administered radioactivity of 592 kBq (or 16 µCi). The total radioactive load for the subject will remain lower than 1000 µSv.