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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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D2 dopamine receptor occupancy (%) vs. quetiapine plasma concentration (IR and XR formulations).
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fig004: D2 dopamine receptor occupancy (%) vs. quetiapine plasma concentration (IR and XR formulations).

Mentions: When using all PET measurements and the concentration of quetiapine measured after administration of IR and XR together, Ki,app was calculated to be 1369 nmol/l (Fig. 4). Ki,app calculated for quetiapine IR only was 1373 nmol/l and for XR only was 1365 nmol/l. Assuming that quetiapine and norquetiapine have the same affinity for the D2 receptor, the sum of the two concentrations was used as an estimate of the active moiety. Ki,app calculated for the active moiety using measurements for both formulations was 2004 nmol/l, and Ki,app calculated for IR and XR separately was 1968 nmol/l and 2041 nmol/l, respectively. The explanatory value of quetiapine and norquetiapine alone or in combination (interaction model) was also tested using nonlinear mixed-effects modelling. Goodness of fit was not improved using the interaction model (results not shown).


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)

D2 dopamine receptor occupancy (%) vs. quetiapine plasma concentration (IR and XR formulations).
© Copyright Policy
Related In: Results  -  Collection

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

fig004: D2 dopamine receptor occupancy (%) vs. quetiapine plasma concentration (IR and XR formulations).
Mentions: When using all PET measurements and the concentration of quetiapine measured after administration of IR and XR together, Ki,app was calculated to be 1369 nmol/l (Fig. 4). Ki,app calculated for quetiapine IR only was 1373 nmol/l and for XR only was 1365 nmol/l. Assuming that quetiapine and norquetiapine have the same affinity for the D2 receptor, the sum of the two concentrations was used as an estimate of the active moiety. Ki,app calculated for the active moiety using measurements for both formulations was 2004 nmol/l, and Ki,app calculated for IR and XR separately was 1968 nmol/l and 2041 nmol/l, respectively. The explanatory value of quetiapine and norquetiapine alone or in combination (interaction model) was also tested using nonlinear mixed-effects modelling. Goodness of fit was not improved using the interaction model (results not shown).

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