Calculating Occupancy when One does not have Baseline: A Comparison of Different Options

Abstract

Dopamine D2 receptor occupancy of antipsychotic drugs is calculated relative to the subject's D2 receptor binding potential (BP) in the drug-free state (baseline BP). Because baseline BP is seldom known in patients with schizophrenia, population means from unrelated control samples are often used to estimate it. However, this is likely to introduce bias and error into the occupancy measure. There is thus a need for a method to reliably estimate baseline BP for patient populations in whom it may be impractical or unethical to get baseline measurements. It has been previously found that the relationship between plasma concentration and dopamine receptor occupancy by antipsychotic drugs follows a sigmoid Emax model. Based on this, we developed a method for calculating dopamine D2 receptor occupancy by antipsychotic drugs using an inhibitory Emax model ( Imax method) that estimates individual baseline BPs. To validate this, we compared the result from the Imax method with actual occupancy and estimated occupancy calculated from the average baseline BP (substitution method). The data for validation were obtained from two different receptor occupancy studies with the antipsychotic medications YKP1358 and aripiprazole. We estimated the reliability between the true measured occupancy and the predicted occupancy using the intraclass correlation coefficient (ICC), and the variability of occupancy was also compared between the Imax and substitution methods. In YKP1358 study, all the ICCs of the Imax method were above 0.8, but those of the substitution method showed values lower than 0.8. In aripiprazole study, the ICCs of the Imax method were higher than those of the substitution method, but all the ICCs showed higher values than 0.8. The variability of Imax method was significantly smaller than that of substitution method in both studies. The Imax method shows better reliability and less variability than the substitution method. The Imax method can be applied for receptor occupancy study, and bring more reliability and accuracy to the occupancy study in patients with schizophrenia.