Brain and Plasma Pharmacokinetics of Aripiprazole in Patients With Schizophrenia: An [ ¹⁸ F]Fallypride PET Study

Objective: Aripiprazole at clinically effective doses occupies some 90% of striatal dopamine 2 and 3 (D ₂ /D ₃ ) receptors. In order to further characterize its extrastriatal and time-dependent binding characteristics, the authors conducted positron emission tomography (PET) studies with the D ₂ /D ₃ antagonist [ ¹⁸ F]fallypride at varying time points after the last aripiprazole administration in patients with schizophrenia. Method: Sixteen inpatients with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder receiving treatment with aripiprazole underwent an [ ¹⁸ F]fallypride PET scan. Receptor occupancy was calculated as the percentage reduction in binding potential relative to unblocked values measured in eight age-matched, medication-free patients with schizophrenia. In addition, aripiprazole serum concentrations were determined as part of a routine therapeutic drug monitoring program in a large group of patients (N=128) treated with aripiprazole. Results: Mean dopamine D ₂ /D ₃ receptor occupancy was high in all brain regions investigated, with no binding difference across brain regions. Nonlinear regression analysis revealed maximum attainable receptor occupancy (E _max ) values close to saturation. The values for serum concentration predicted to provide 50% of E _max (EC ₅₀ ) were in the range of 5–10 ng/ml in all brain regions. The D ₂ /D ₃ receptors were completely saturated when serum aripiprazole concentration exceeded 100–150 ng/ml. The mean concentration in the large clinical patient sample was 228 ng/ml (SD=142). Conclusions: Because of its high affinity for D ₂ /D ₃ receptors and its long elimination half-life, aripiprazole at clinical doses occupies a high fraction of its target receptor everywhere in the brain. Its dissociation from those receptors is very slow, such that the authors calculate from the results that in patients with serum aripiprazole concentrations in the range typical for clinical practice, D ₂ /D ₃ receptors must remain nearly saturated for as long as 1 week after the last dose.