Dopamine D_2/3 Receptor Occupancy Following Dose Reduction Is Predictable with Minimal Plasma Antipsychotic Concentrations: An Open-Label Clinical Trial

Background. Population pharmacokinetics can predict antipsychotic blood concentrations at a given time point prior to a dosage change. Those predicted blood concentrations could be used to estimate the corresponding dopamine D_2/3 receptors (D_2/3R) occupancy by antipsychotics based on the tight relationship between blood and brain pharmacokinetics. However, this 2-step prediction has never been tested. Methods. Two blood samples were collected at separate time points from 32 clinically stable outpatients with schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; mean ± SD age: 60.1±7.3 years) to measure plasma concentrations of olanzapine or risperidone at baseline. Then, subjects underwent a dose reduction of olanzapine or risperidone and completed a [¹¹C]-raclopride positron emission tomography scan to measure D_2/3R occupancy in the putamen. The plasma concentration at the time of the scan was predicted with the 2 samples based on population pharmacokinetic model, using NONMEM. D_2/3R occupancy was then estimated by incorporating the predicted plasma concentration in a hyperbole saturation model. The predicted occupancy was compared to the observed value. Results. The mean (95% CI) prediction errors for the prediction of D_2/3R occupancy were -1.76% (-5.11 to 1.58) for olanzapine and 0.64% (-6.18 to 7.46) for risperidone. The observed and predicted D_2/3R occupancy levels were highly correlated (r = 0.67, P =. 001 for olanzapine; r = 0.67, P =. 02 for risperidone). Conclusions. D_2/3R occupancy levels can be predicted from blood drug concentrations collected prior to dosage change. Although this 2-step model is subject to a small degree of error, it could be used to select oral doses aimed at achieving optimal D_2/3R occupancy on an individual basis.