Predicting the dopamine D₂ receptor occupancy of ropinirole in rats using positron emission tomography and pharmacokinetic–pharmacodynamic modeling

Abstract

1. The purpose of this study was to measure dopamine D_2/3 receptor occupancy (RO) as a marker of the clinical efficacy of ropinirole in rats via positron emission tomography (PET) using ¹⁸F-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 ¹⁸F-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. ¹⁸F-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.

Keywords:

• Dopamine agonist
• positron emission tomography
• receptor occupancy
• pharmacodynamics
• pharmacokinetics

Acknowledgments

We are very grateful for the contributions of Ling Xue, Shichao Zhang, Jincheng Liu and Bohua Xu in assisting with the research, and Prof. Ji Jiang for providing valuable advice.

Disclosure statement

We declare that we have no conflicts of interest.

This work was supported by the National Natural Science Foundation of China [No. 81503159 and No. 81403015] and the National Key New Drug Creation Special Programs (2017ZX09304-021).