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

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 (D ₂RO) and plasma concentration (C _P) in stabilized schizophrenic patients on clinically relevant doses using ¹²³I-IBZM SPECT; 2) To investigate the time course of AP-induced D₂RO and corresponding C _P. Forty-six schizophrenic patients on their clinically required doses of risperidone, olanzapine, clozapine or quetiapine were included. D ₂RO and C _P 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 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—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 C _P 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.