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

Nord M, Nyberg S, Brogren J, Jucaite A, Halldin C, Farde L - Int. J. Neuropsychopharmacol. (2011)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Psychiatry Section, Karolinska University Hospital, Stockholm, Sweden. Magdalena.Nord@ki.se

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.

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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.
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fig002: 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.

Mentions: The PET measurements were performed close to the observed peak concentrations of quetiapine and norquetiapine, respectively. The time difference between the start time of the PET peak measurements and Tmax of quetiapine were: IR (0.14±0.43 h, range −0.55 to 0.9) and XR (0.12±2.6 h, range −6.76 to 2.24). Thus, a larger range was noted for the XR formulation, but the more blunted plasma concentration curve with this formulation makes the timing of the PET measurement less sensitive to deviations from Tmax. The difference between quetiapine Cmax and the plasma concentration measured during the peak PET measurements (Cav,PET,peak) was not statistically significant for either formulation (IR: Cmax 1850±820 vs. Cav,PET,peak 1460±510, d.f.=13.3, t=1.20, p=0.25; XR: Cmax 894±380 vs. Cav,PET,peak 719±310, d.f.=17.2, t=1.13, p=0.27). In all subjects, D2 receptor occupancy was higher at IR peak compared to XR peak (Figs 2 and 3). The mean D2 receptor occupancy in the putamen at peak concentration was 50±4% for quetiapine IR (n=9) and 32±11% for XR (n=11). The difference was statistically significant (d.f.=13.5, t=4.89, p=0.0003). There was no significant difference in D2 receptor occupancy at trough levels between the two formulations [IR 7±7% (n=10), XR 8±6% (n=10); d.f.=17.6, t=0.41, p=0.7]. In two subjects, trough occupancy even reached negative values (−1% at XR trough for one subject and −3% at IR trough for another subject). However, this minor negativity was within the range for test–retest reliability.


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

Nord M, Nyberg S, Brogren J, Jucaite A, Halldin C, Farde L - Int. J. Neuropsychopharmacol. (2011)

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.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3198174&req=5

fig002: 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.
Mentions: The PET measurements were performed close to the observed peak concentrations of quetiapine and norquetiapine, respectively. The time difference between the start time of the PET peak measurements and Tmax of quetiapine were: IR (0.14±0.43 h, range −0.55 to 0.9) and XR (0.12±2.6 h, range −6.76 to 2.24). Thus, a larger range was noted for the XR formulation, but the more blunted plasma concentration curve with this formulation makes the timing of the PET measurement less sensitive to deviations from Tmax. The difference between quetiapine Cmax and the plasma concentration measured during the peak PET measurements (Cav,PET,peak) was not statistically significant for either formulation (IR: Cmax 1850±820 vs. Cav,PET,peak 1460±510, d.f.=13.3, t=1.20, p=0.25; XR: Cmax 894±380 vs. Cav,PET,peak 719±310, d.f.=17.2, t=1.13, p=0.27). In all subjects, D2 receptor occupancy was higher at IR peak compared to XR peak (Figs 2 and 3). The mean D2 receptor occupancy in the putamen at peak concentration was 50±4% for quetiapine IR (n=9) and 32±11% for XR (n=11). The difference was statistically significant (d.f.=13.5, t=4.89, p=0.0003). There was no significant difference in D2 receptor occupancy at trough levels between the two formulations [IR 7±7% (n=10), XR 8±6% (n=10); d.f.=17.6, t=0.41, p=0.7]. In two subjects, trough occupancy even reached negative values (−1% at XR trough for one subject and −3% at IR trough for another subject). However, this minor negativity was within the range for test–retest reliability.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Psychiatry Section, Karolinska University Hospital, Stockholm, Sweden. Magdalena.Nord@ki.se

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.

Show MeSH
Related in: MedlinePlus