A Study of Paliperidone Enantiomer Disposition With Different Formulations and the Bioavailability of Immediate- and Extended-release Paliperidone

This is a single-center, single-dose, open-label, randomized, crossover study in healthy adults, following a 5-sequence, 5-treatment, 5-period Latin square design. The study consists of a screening phase (within 21 days before the first administration of study drug), and a treatment phase consisting of 5 periods during which volunteers will receive a single dose of study drug under fasting conditions \[orally with 240 mL of water or intravenously (i.v.)\] in a random order. Pharmacokinetic blood and urine samples will be collected over a 96-hour period following study drug administration during each treatment period. Volunteers will be confined to the testing facility from at least 10 hours before dosing until 72 hours after dosing in each treatment period and will return for additional assessments. Each administration of study drug will be separated by a washout period of at least 7 to a maximum of 14 days. The duration of volunteer participation is maximally 12 weeks, including the 3 week screening period. CYP2D6 metabolizer status will be assessed by phenotyping and will be corroborated by genotyping of a DNA sample to be collected from volunteers who consent to this part of the study. Pharmacokinetic data are available after oral administration of immediate release and extended release formulations of paliperidone. No data are available after i.v. administration of paliperidone. The data obtained in this study for the i.v. route are important to further characterize the pharmacokinetics of paliperidone, and for future population pharmacokinetics modeling of paliperidone. For chiral substances, it is requested by regulatory authority guidelines to document the disposition of the enantiomers. Therefore, the disposition of the (+) and (-) enantiomers of paliperidone for different administration routes (i.v. and oral) and formulations (immediate release and extended release \[ER OROS\]) will be documented. Separate enantiomers will be administered in this study, as it is important for the full understanding of the pharmacokinetics of paliperidone to document the possible chiral interconversion. Safety and tolerability will be monitored throughout the study. 5 single doses, one each of: Treatment A, 1 mg IR paliperidone oral solution; Treatment B, 3 mg ER OROS paliperidone oral; Treatment C, 1 mg paliperidone as a 30-min i.v. infusion; Treatment D, 1 mg (+)-paliperidone (R078543) oral solution; and Treatment E, 1 mg (-)-paliperidone (R078544) oral solution.