A Study of Paliperidone Enantiomer Disposition With Different Formulations and the Bioavailability of Immediate- and Extended-release Paliperidone
Condition: Schizophrenia
MeSH terms: Schizophrenia
Study type: Interventional
Phase: Phase 1

Summary: 
      The purpose of this study is to characterize the pharmacokinetics of paliperidone in plasma
      and urine after intravenous (i.v.) administration of the racemate, administration of the
      immediate-release (IR) racemate oral solution, administration of the ER OROS tablet, and
      administration of the oral solutions of the individual enantiomers R078543 (+) and R078544
      (-); to determine the absolute oral bioavailability of IR and ER OROS paliperidone; to
      document the (+) and (-) paliperidone enantiomer ratio after i.v. and oral administration (IR
      and ER OROS paliperidone); to document the possible interconversion between the (+) and (-)
      enantiomers of paliperidone after oral treatment with the separate enantiomers; to document
      the possible relationship between the subject's CYP2D6 phenotype and the (+) and (-)
      enantiomer disposition of paliperidone (CYP2D6 genotyping was used to corroborate the
      phenotype). In addition, the safety and tolerability of all treatments will be evaluated.
    

Detailed description: 
      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.
    

Intervention name(s): IR OROS paliperidone and ER OROS paliperidone
Intervention type(s): Drug
Intervention MeSH terms: Paliperidone Palmitate
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Schizophrenia; Mood disorders; Antipsychotics; Pharmacokinetics; Enantiomer; IR OROS Paliperidone; ER OROS Paliperidone