Dopamine D₂/₃ occupancy of ziprasidone across a day: a within-subject PET study

Abstract

Rationale: Ziprasidone is an atypical antipsychotic recommended to be administered twice daily.

Objectives: The purpose of this study was to investigate whether occupancy of the dopamine D2/3 receptors by ziprasidone is maintained across a day employing a within subject design.

Methods: Positron emission tomography (PET) scans with [(11)C]-raclopride were performed in 12 patients with schizophrenia while treated with ziprasidone 60 mg twice daily. Each patient completed [(11)C]-raclopride PET scans at 5, 13 and 23 h after the last dose of ziprasidone. Dopamine D2/3 receptor occupancy was estimated with reference to binding potential data of 44 age- and sex-matched control subjects in the caudate, putamen and ventral striatum.

Results: Eleven scans were available at each time point, and the mean occupancies at 5-, 13- and 23-h scans were 66, 39 and 2 % in the putamen; 62, 35 and -6 % in the caudate; and 68, 47 and 11 % in the ventral striatum, respectively. The time-course of receptor occupancy across the regions indicated an occupancy half-life of 8.3 h. The serum level of ziprasidone associated with 50 % D2/3 receptors occupancy was estimated to be 204 nmol/L (84 ng/ml). Prolactin levels were highest at 5-h post-dose and none showed hyperprolactinemia at 23-h scans.

Conclusions: The absence of ziprasidone striatal D2/3 receptor binding 23 h after taking 60 mg under steady-state conditions is consistent with its peripheral half-life. The results support our earlier report that ziprasidone 60 mg administered twice daily appears to be the minimal dose expected to achieve therapeutic central dopamine D2/3 receptor occupancy (i.e. 60 %).

Clinical trials registration: 24-Hour Time Course of Striatal Dopamine D2 Receptor Occupancy of Ziprasidone: A PET Study, www.clinicaltrials.gov/ct2/show/NCT00818298 , NCT00818298.

Conflict of interest statement

Conflicts of interest:

This study was supported by an investigator initiated research grant from Pfizer Canada Inc. Dr. Suzuki has received manuscript or speaker’s fees from Dainippon Sumitomo Pharma, Eli Lilly, Astellas, Meiji Seika Pharma and Novartis Pharma. Dr. Graff-Guerrerro currently receives research support from the following external funding agencies: Canadian Institutes of Health Research (CIHR), the US National Institute of Health (NIH), Ontario Mental Health Foundation, Mexico ICyTDF and CONACyT. Dr. Uchida has received grants from Pfizer and Dainippon-Sumitomo Pharma, and speaker’s honoraria from Otsuka Pharmaceutical, Eli Lilly, Novartis Pharma, Shionogi, GlaxoSmithKline, Yoshitomi Yakuhin, Dainippon-Sumitomo Pharma, and Janssen Pharmaceutical within the past 2 years. Dr. Gary Remington, in the last 3 years, has received research support (Principal Investigator) from the following external funding agencies: CIHR, Research Hospital Fund - Canada Foundation for Innovation GUF- CFI), Schizophrenia Society of Ontario (SSO), and the Canadian Diabetes Association (CDA). He has also received support from Novartis Canada Medicure Inc., and Neurocrine Bioscience. He has received consultant fees from Laboratorios Farmacduticos ROVI, Novartis, and Roche, as well as speaker’s fees from Novartis. He holds no commercial investments in any pharmaceutical company. Mr. Caravaggio and Ms. Borlido have nothing to disclose. Dr. Pollock receives research support from the US NIH, CIHR, American Psychiatric Association and the Foundation of the Centre for Addiction and Mental Health. Dr Mulsant currently receives research support from the CIHR, the US NIH, Bristol-Myers Squibb (medications for a NIH-funded clinical trial), and Pfizer (medications for a NIH-funded clinical trial). He directly owns stocks of General Electric (less than $5, 000). Within the past five years he has also received some grant support from Eli Lilly (medications for a NIH-funded clinical trial) and Janssen and some travel support from Roche. Dr. DeLuca has nothing to disclose. Dr. Ismail received support as consultant for Sunovion, BMS, Pfizer and Lundbeck. He also received research support form Pfizer and has honoraria from Otsuka, Lundbeck and Pfizer. Dr. Mamo currently receives research support from the following external funding agencies: CIHR, the US NIH, Ontario Ministry of Health and Long Term Care. He has also received grants or consultant fees from the Bristol-Myers Squibb and Pfizer and has received speaker’s honoraria from AstraZeneca in the past 3 years.

Figures

Figure 1

Serum ziprasidone level before and after each PET scan. Each symbol represents the same individual.

Figure 2

Relationship between ziprasidone serum levels and D2 receptor occupancy in regions of interest. The line corresponds to the fitting to one-site binding model across the regions of interest (ED50 = 204 nmol/L, R2 = 0.68). The occupancies in negative values were excluded from the graph and no considered to estimate the ED50.

Figure 3

[11C]-raclopride binding potential non-displaceable maps. Images correspond to averaged [11C]-raclopride binding potential maps of healthy controls (n=44) and patients with schizophrenia after 5-hour (n=11), 13-hour (n=11) and 23-hour (n=11) of the last dose of ziprasidone (60 mg). The binding potential maps are presented with an absolute threshold between 0 and 7 and in axial projection illustrating the dorsal striatum regions.