Comparison of D₂ dopamine receptor occupancy after oral administration of quetiapine fumarate immediate-release and extended-release formulations in healthy subjects

Magdalena Nord, Svante Nyberg, Jacob Brogren, Aurelija Jucaite, Christer Halldin, Lars Farde, Magdalena Nord, Svante Nyberg, Jacob Brogren, Aurelija Jucaite, Christer Halldin, Lars Farde

Abstract

Quetiapine is an established drug for treatment of schizophrenia, bipolar disorder, and major depressive disorder. While initially manufactured as an immediate-release (IR) formulation, an extended-release (XR) formulation has recently been introduced. Pharmacokinetic studies show that quetiapine XR provides a lower peak and more stable plasma concentration than the IR formulation. This study investigated if the pharmacokinetic differences translate into different time curves for central D₂ dopamine receptor occupancy. Eleven control subjects were examined with positron emission tomography (PET) and the radioligand [11C]raclopride. Eight subjects underwent all of the scheduled PET measurements. After baseline examination, quetiapine XR was administered once-daily for 8 d titrated to 300 mg/d on days 5-8, followed by 300 mg/d quetiapine IR on days 9-12. PET measurements were repeated after the last doses of quetiapine XR and IR at predicted times of peak and trough plasma concentrations. Striatal D₂ receptor occupancy was calculated using the simplified reference tissue model. Peak D₂ receptor occupancy was significantly higher with quetiapine IR than XR in all subjects (50 ± 4% and 32 ± 11%, respectively), consistent with lower peak plasma concentrations for the XR formulation. Trough D₂ receptor occupancy was similarly low for both formulations (IR 7 ± 7%, XR 8 ± 6%). The lower peak receptor occupancy associated with quetiapine XR may explain observed pharmacodynamic differences between the formulations. Assuming that our findings in control subjects are valid for patients with schizophrenia, the study supports the view that quetiapine, like the prototype atypical antipsychotic clozapine, may show antipsychotic effect at lower D₂ receptor occupancy than typical antipsychotics.

Trial registration: ClinicalTrials.gov NCT00832221.

Figures

Fig. 1
Fig. 1
Arithmetic mean plasma concentration of quetiapine and norquetiapine during quetiapine IR (left) and XR (right) administration.
Fig. 2
Fig. 2
Parametric horizontal PET images through the caudate putamen level showing the binding potential after intravenous injection of [11C]raclopride in a human subject at baseline conditions and after administration of quetiapine IR and XR, respectively.
Fig. 3
Fig. 3
D2 dopamine receptor occupancy (%) in 11 subjects after administration of quetiapine IR and XR, respectively.
Fig. 4
Fig. 4
D2 dopamine receptor occupancy (%) vs. quetiapine plasma concentration (IR and XR formulations).
Fig. 5
Fig. 5
Estimated D2 dopamine receptor occupancy (%) vs. time for quetiapine IR (left) and XR (right) formulations. The solid lines describe the occupancy time curve for a typical individual. The grey areas represent the 95% prediction intervals.

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