Ocupacion Receptores D2 -Quetiapina

International Journal of Neuropsychopharmacology (2011), 14, 1357–1366. f CINP and Cambridge University Press 2011 doi:10.1017/S1461145711000514

ARTICLE

Comparison of D2 dopamine receptor occupancy after oral administration of quetiapine fumarate immediate-release and extended-release formulations in healthy subjects
Magdalena Nord1, Svante Nyberg2, Jacob Brogren2, Aurelija Jucaite2,Christer Halldin1 and Lars Farde1,2
1

Karolinska Institutet, Department of Clinical Neuroscience, Psychiatry Section, Karolinska University Hospital, Stockholm, Sweden 2 AstraZeneca Pharmaceuticals Clinical Neuroscience, Sodertalje, Sweden ¨ ¨

Abstract Quetiapine is an established drug for treatment of schizophrenia, bipolar disorder, and major depressive disorder. While initially manufacturedas 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 controlsubjects 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 atpredicted 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 forboth 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 atlower D2 receptor occupancy than typical antipsychotics. Received 21 December 2010 ; Reviewed 10 January 2011 ; Revised 10 February 2011 ; Accepted 28 February 2011 ; First published online 11 April 2011 Key words : D2 dopamine receptor, PET, quetiapine.

Introduction Quetiapine is an atypical antipsychotic drug with efficacy demonstrated in clinical trials for the treatment of schizophrenia, bipolardisorder, major depressive disorder, and generalized anxiety disorder. The clinical effects are thought to be mediated by both

Address for correspondence : Miss M. Nord, Karolinska Institutet, Department of Clinical Neuroscience, Psychiatry Section, R5 : 00, Karolinska University Hospital, SE-17176 Stockholm, Sweden. Tel. : +46 8 517 73720 Fax : +46 8 517 717 53 Email : Magdalena.Nord@ki.sequetiapine and its main active human metabolite, norquetiapine (Jensen et al. 2008). Quetiapine in its original immediate-release (IR) formulation has a short half-life (7 h) (Nemeroff et al. 2002) and twicedaily administration is recommended for the treatment of schizophrenia and bipolar mania. To allow for once-daily dosing, an extended-release (XR) formulation has more recently been developed.Pharmacokinetic studies have shown that, when given in equivalent daily doses, the exposure in terms of area under the curve (AUC) of the two compounds is comparable. Whereas the XR formulation has a slightly lower peak plasma concentration (Cmax) than the

The online version of this article is published within an Open Access environment subject to the conditions of the Creative Commons...