A Pharmacokinetic Study of the Relative Bioavailability of Paliperidone ER Formulations With Different Release Profiles and a Comparison to Paliperidone IR
A Pharmacokinetic Study of the Relative Bioavailability of Paliperidone ER Formulations With Different Release Profiles and a Comparison to Paliperidone IR
The primary purpose of this study is to evaluate the pharmacokinetics and relative
 bioavailability of paliperidone ER formulations with slow, target, and fast in vitro release
 rates after administration of a single 12 mg dose. The slow and fast releasing ER tablets
 have in vitro release rates outside the current commercial specifications. Therefore, in
 order to support widening of the specification limits, this study will be performed. The
 target formulation to be used is representative of the commercial formulation. Other
 objectives of this study are 1) to compare the relative bioavailability of paliperidone ER
 formulations with slow, target, and fast in vitro release rates to the paliperidone IR
 formulation; 2) to explore the in vitro in vivo correlation (IVIVC) for the paliperidone ER
 formulation; and 3) to evaluate the safety and tolerability of the different paliperidone ER
 formulations.
This is a randomized, open-label, 4-way crossover, single dose study in healthy male
 volunteers to evaluate the pharmacokinetic profiles of paliperidone ER tablets with slow,
 target, and fast in vitro release rates and paliperidone IR. The study consists of a 21 day
 screening phase, an open-label treatment phase consisting of 4 single-dose treatment periods
 (IR, slow, fast, and target formulations), and an end-of-study or early withdrawal phase. A
 10- to 21 day washout period (i.e., >5 times the half-life) will separate each study drug
 administration (i.e., each open label treatment period). In the first period, all volunteers
 are given a 1-mg dose of paliperidone IR solution, administered as a single oral dose under
 fasted conditions (Treatment A). On Day 1 of Period 2, prior to study drug administration,
 all volunteers will be randomly assigned to 1 of 6 possible treatment sequences to ensure
 that they receive all of the following treatments, one in each period: 12-mg paliperidone ER
 tablet with a target in vitro release under fasted condition (Treatment B); 12-mg
 paliperidone ER tablet with a slow in vitro release under fasted condition (Treatment C);
 12-mg paliperidone ER tablet with a fast in vitro release under fasted condition (Treatment
 D). In each treatment period, volunteers will enter the study center at least 10 hours before
 the study drug administration on Day 1 and will remain there until after collection of the 96
 hour pharmacokinetic samples on Day 5 if the investigator considers that the volunteer is
 ready for discharge. It is expected that the differences in the in vitro release rate will
 not affect the relative bioavailability of paliperidone in vivo. Safety and tolerability of
 the different paliperidone ER formulations will be monitored throughout the study.

 Single oral doses of paliperidone ER 12 mg tablets with different release rates (target,
 fast, and slow); single oral dose of paliperidone IR 1 mg
Inclusion Criteria:

 -  Must agree to use an efficient method of birth control as deemed appropriate by the
 investigator and to not donate sperm during the study and for 3 months after receiving
 the last dose of study drug

 -  Body mass index (weight [kg]/height [m2]) between 18 and 30 kg/m2 (inclusive), and
 body weight not less than 50 kg

 -  Blood pressure (after the volunteer is supine for 5 minutes) between 100 and 140 mmHg
 systolic, inclusive, and between 50 and 90 mmHg diastolic. Pulse rate measured over 60
 seconds should be between 40 and 100 beats per minute (bpm)

 -  Non-smoker

 Exclusion Criteria:

 -  History of or current significant medical illness including (but not limited to)
 cardiac arrhythmias or other cardiac disease, hematologic disease, coagulation
 disorders (including any abnormal bleeding or blood dyscrasias), lipid abnormalities,
 significant pulmonary disease, including bronchospastic respiratory disease, diabetes
 mellitus, renal or hepatic insufficiency, thyroid disease, neurologic or psychiatric
 disease, infection, or any other illness that the investigator considers should
 exclude the volunteer

 -  History or presence of circumstances that may increase the risk of the occurrence of
 torsade de pointes and/or sudden death in association with the use of drugs that
 prolong the QTc interval, including: bradycardia (heart rate < 40 bpm on the ECG),
 clinically significant abnormality on the ECG, demonstration of repeated prolonged
 QTcF > 450 ms (QTc interval corrected for heart rate using Fridericia's formula), as
 measured on more than one ECG (either during screening, or from prior medical record)

 -  The following cardiac conditions: sick sinus syndrome, complete AV block, congestive
 heart failure, polymorphic ventricular tachycardia

 -  Clinically relevant hypocalcemia, hypokalemia or hypomagnesemia

 -  Presence of congenital prolongation of the QT interval (Romano-Ward Syndrome, Jervell
 and Lange-Nielsen syndrome)

 -  History of any cancer, with the exception of basal cell carcinoma: Clinically
 significant abnormal values for hematology, clinical chemistry or urinalysis at
 screening or at admission to the study center, in the opinion of the investigator

 -  Clinically significant abnormality on physical examination, in the opinion of the
 investigator

 -  At screening, has signs of orthostatic hypotension defined as a decrease in systolic (
 > 20 mmHg) or diastolic (> 10 mmHg) blood pressure after standing for at least 2
 minutes, that is associated with an increase in pulse rate of >15 bpm compared with
 supine measurements

 -  Use of any prescription or nonprescription medication (including vitamins and herbal
 supplements), except for paracetamol (acetaminophen) or ibuprofen, within 14 days
 before the first dose of the study drug is scheduled