Predicting the dopamine D 2 receptor occupancy of ropinirole in rats using positron emission tomography and pharmacokinetic-pharmacodynamic modeling.

1. The purpose of this study was to measure dopamine D2/3 receptor occupancy (RO) as a marker of the clinical efficacy of ropinirole in rats via positron emission tomography (PET) using 18 F-fallypride as the radiotracer and to explore the relationship between dopamine RO and the plasma concentration of ropinirole via pharmacokinetic-pharmacodynamic modeling. 2. Plasma was collected from 16 rats treated with one of four doses of ropinirole. For the time-dependent study, the data of 16 rats in the 15 mg/kg dose group at four time points were averaged, and another 24 rats were divided into three dose groups (5 mg/kg, 30 mg/kg and 60 mg/kg) for the dose-dependent study; the animals were assessed via 18 F-fallypride PET scans. The correlation between dopamine RO and the ropinirole plasma concentration was investigated, and a pharmacokinetic-pharmacodynamic (PK-PD) model was established with WinNonlin 6.3 software. Both the plasma concentration and the binding potential changed in a time- and dose-dependent manner, and the plasma concentration that induces 50% RO (EC50 ) as calculated by the PK-PD model was 1391 ng/mL. 3. 18 F-fallypride appeared to be a suitable radiotracer for ropinirole imaging, and its binding to the dopamine D2 receptor has time- and concentration-dependent characteristics. A theory-based PK-PD model was developed to describe the relationship between the plasma ropinirole concentration and RO, providing a methodological foundation for noninvasive and in vivo clinical evaluations of ropinirole treatment.