title: Pharmacokinetics and time-course of D(2) receptor occupancy induced by atypical antipsychotics in stabilized schizophrenic patients.
abstract: The (123)I-IBZM SPECT measured D(2) receptor occupancy (D(2)RO) in chronically dosed, stabilized schizophrenic patients and its relationship with antipsychotic (AP) pharmacokinetics (PK) over time is still unclear. The aims of this study were: 1) To define the relationship between striatal D(2) receptor occupancy (D( 2)RO) and plasma concentration (C(P)) in stabilized schizophrenic patients on clinically relevant doses using (123)I-IBZM SPECT; 2) To investigate the time course of AP-induced D(2)RO and corresponding C(P). Forty-six schizophrenic patients on their clinically required doses of risperidone, olanzapine, clozapine or quetiapine were included. D( 2)RO and C(P) were measured over time following a sparse-sampling experimental design, and individual PK and D(2)RO-time profiles were estimated using a population approach. Observed striatal D(2)RO and C(P) ranges were 28-75% and 9.4-60.5 ng/mL for risperidone, 22-84% and 8.6-89.5 ng/mL for olanzapine, 5-53% and 41.6-818.2 ng/mL for clozapine and 0-64% and 37.9-719.6 ng/mL for quetiapine. A PK-D(2)RO relationship was found for the four APs. D(2)RO pattern over time was stable for risperidone, olanzapine and clozapine but fluctuating for quetiapine. Stabilized schizophrenic patients show a wide range of both D(2)RO and C(P) at clinically effective doses of the four AP, suggesting that clinical response to these AP may be maintained with D(2)RO below 65%. D(2)RO patterns over time differ between AP. These results should be considered for accurate interpretation of D(2)RO measurements, proper design of studies and optimization of drug regimens for patients on AP treatment.
authors.affiliation: Experimental Medical Sciences, Clinical Pharmacology Discovery Medicine, Psychiatry Centre of Excellence for Drug Discovery, GlaxoSmithKline, Barcelona, Spain. ana.m.catafau@gsk.com
authors.forename: A M
authors.initials: AM
authors.lastname: Catafau
authors.forename: M M
authors.initials: MM
authors.lastname: Penengo
authors.forename: G
authors.initials: G
authors.lastname: Nucci
authors.forename: S
authors.initials: S
authors.lastname: Bullich
authors.forename: I
authors.initials: I
authors.lastname: Corripio
authors.forename: E
authors.initials: E
authors.lastname: Parellada
authors.forename: C
authors.initials: C
authors.lastname: García-Ribera
authors.forename: R
authors.initials: R
authors.lastname: Gomeni
authors.forename: E
authors.initials: E
authors.lastname: Merlo-Pich
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D001549:Benzamides; D005260:Female; D006801:Humans; D008297:Male; D011759:Pyrrolidines; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy*; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D014150:Antipsychotic Agents; D001549:Benzamides; D011759:Pyrrolidines; D017448:Receptors, Dopamine D2; C055743:3-iodo-2-hydroxy-6-methoxy-N-((1-ethyl-2-pyrrolidinyl)methyl)benzamide