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Pharmacokinetics and time–course of D₂ receptor occupancy induced by atypical antipsychotics in stabilized schizophrenic patients

¹ Experimental Medical Sciences, Clinical Pharmacology Discovery Medicine, Psychiatry Centre of Excellence for Drug Discovery, GlaxoSmithKline, Barcelona, Spain and Verona, Italy and Centre for Imaging in Psychiatry, CRC–Mar, Hospital del Mar, Barcelona, Spain.
² Centre for Imaging in Psychiatry, CRC–Mar, Hospital del Mar, Barcelona, Spain.
³ Clinical Pharmacokinetics Modelling and Simulation, Psychiatry, GlaxoSmithKline, Verona, Italy.
⁴ Psychiatry Department, Red de Enfermedades Mentales–Trastornos Afectivos y Psicóticos (REM–TAP Network) Hospital de Sant Pau, Barcelona, Spain.
⁵ Psychiatry Department, Clinic Schizophrenia Program, Hospital Clinic i Provincial, Barcelona, Spain.
⁶ Mental Health and Drug Addiction Department, Hospital del Mar and Psychiatry Institute, IMAS, Barcelona, Spain.
⁷ Experimental Medical Sciences, Clinical Pharmacology Discovery Medicine, Psychiatry Centre of Excellence for Drug Discovery, GlaxoSmithKline, Barcelona, Spain and Verona, Italy.

^* To whom correspondence should be addressed.

	Abstract

The 123I–IBZM SPECT measured D2 receptor occupancy (D2RO) 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 D2 receptor occupancy (D2RO) and plasma concentration (CP) in stabilized schizophrenic patients on clinically relevant doses using 123I–IBZM SPECT; 2) To investigate the time course of AP–induced D2RO and corresponding CP. Forty–six schizophrenic patients on their clinically required doses of risperidone, olanzapine, clozapine or quetiapine were included. D2RO and CP were measured over time following a sparse–sampling experimental design, and individual PK and D2RO–time profiles were estimated using a population approach. Observed striatal D2RO and CP 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–D2RO relationship was found for the four APs. D2RO pattern over time was stable for risperidone, olanzapine and clozapine but fluctuating for quetiapine. Stabilized schizophrenic patients show a wide range of both D2RO and CP at clinically effective doses of the four AP, suggesting that clinical response to these AP may be maintained with D2RO below 65%. D2RO patterns over time differ between AP. These results should be considered for accurate interpretation of D2RO measurements, proper design of studies and optimization of drug regimens for patients on AP treatment.

Key Words: schizophrenia, D2 receptor, PK–PD model, atypical, antipsychotics, SPECT

First published on February 28, 2008, doi:10.1177/0269881107083810

Journal of Psychopharmacology 2008;22:882.

A more recent version of this article appeared on November 1, 2008


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