Dose-finding study of paliperidone ER based on striatal and extrastriatal dopamine D2 receptor occupancy in patients with schizophrenia.
BACKGROUND
Paliperidone ER is a novel antipsychotic drug in an extended-release (ER) formulation. As with all antipsychotics, careful dose setting is necessary to avoid side effects.


OBJECTIVE
In this study, we measured striatal and extrastriatal dopamine D2 receptor occupancy during paliperidone ER treatment in patients with schizophrenia using positron emission tomography (PET) to compare regional occupancy and to estimate the optimal dose.


METHODS
Thirteen male patients with schizophrenia participated in this 6-week multiple-dose study. Six of them took 3 mg of paliperidone ER per day, four took 9 mg, and three took 15 mg. Two to 6 weeks after first drug intake, two PET scans, one with [11C]raclopride and one with [11C]FLB 457, were performed in each patient on the same day. The relationship between the dose or plasma concentration of paliperidone and dopamine D2 receptor occupancy was calculated.


RESULTS
The dopamine D2 receptor occupancies in the striatum measured with [11C]raclopride and the temporal cortex measured with [11C]FLB 457 were 54.2-85.5% and 34.5-87.3%, respectively. ED50 values of the striatum and temporal cortex were 2.38 and 2.84 mg/day, respectively. There was no significant difference in dopamine D2 receptor occupancy between the striatum and the temporal cortex.


CONCLUSIONS
The data from this study suggest that paliperidone ER at 6-9 mg provides an estimated level of dopamine D2 receptor occupancy between 70-80% and that the magnitude of dopamine D2 receptor occupancy is similar between the striatum and temporal cortex.
Department of Molecular Neuroimaging, Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1, Anagawa, Inage-ku, Chiba 263-8555, Japan.
Ryosuke
R
Arakawa
Hiroshi
H
Ito
Akihiro
A
Takano
Hidehiko
H
Takahashi
Takuya
T
Morimoto
Takeshi
T
Sassa
Katsuya
K
Ohta
Motoichiro
M
Kato
Yoshiro
Y
Okubo
Tetsuya
T
Suhara
D000328:Adult; D014150:Antipsychotic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001923:Brain Chemistry / Q000187:drug effects*; D003627:Data Interpretation, Statistical; D003692:Delayed-Action Preparations; D018492:Dopamine Antagonists; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007555:Isoxazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D017072:Neostriatum / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D000068882:Paliperidone Palmitate; D049268:Positron-Emission Tomography; D011569:Psychiatric Status Rating Scales; D011743:Pyrimidines / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011759:Pyrrolidines; D020891:Raclopride; D019275:Radiopharmaceuticals; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism*; D012457:Salicylamides; D012559:Schizophrenia / Q000000981:diagnostic imaging / Q000188:drug therapy*
D014150:Antipsychotic Agents; D003692:Delayed-Action Preparations; D018492:Dopamine Antagonists; D007555:Isoxazoles; D011743:Pyrimidines; D011759:Pyrrolidines; D019275:Radiopharmaceuticals; D017448:Receptors, Dopamine D2; D012457:Salicylamides; C065065:FLB 457; D020891:Raclopride; D000068882:Paliperidone Palmitate