An open-label, positron emission tomography study of the striatal D 2 /D 3 receptor occupancy and pharmacokinetics of single-dose oral brexpiprazole in healthy participants.

Purpose: The aim of this Phase 1, open-label, positron emission tomography (PET) study was to determine the degree of striatal D ₂ /D ₃ receptor occupancy induced by the serotonin-dopamine activity modulator, brexpiprazole, at different single dose levels in the range 0.25-6 mg.
Methods: Occupancy was measured at 4 and 23.5 h post-dose using the D ₂ /D ₃ receptor antagonist [ ¹¹ C]raclopride. The pharmacokinetics, safety and tolerability of brexpiprazole were assessed in parallel.
Results: Fifteen healthy participants were enrolled (mean age 33.9 years; 93.3% male). Mean D ₂ /D ₃ receptor occupancy in the putamen and caudate nucleus increased with brexpiprazole dose, leveled out at 77-88% with brexpiprazole 5 mg and 6 mg at 4 h post-dose, and remained at a similar level at 23.5 h post-dose (74-83%). Estimates of maximum obtainable receptor occupancy (O _max ) were 89.2% for the putamen and 95.4% for the caudate nucleus; plasma concentrations predicted to provide 50% of O _max (EC ₅₀ ) were 8.13 ng/mL and 7.75 ng/mL, respectively. Brexpiprazole area under the concentration-time curve (AUC _∞ ) and maximum plasma concentration (C _max ) increased approximately proportional to dose. No notable subjective or objective adverse effects were observed in this cohort.
Conclusion: By extrapolating the observed single-dose D ₂ /D ₃ receptor occupancy data in healthy participants, multiple doses of brexpiprazole 2 mg/day and above are expected to result in an efficacious brexpiprazole concentration, consistent with clinically active doses in schizophrenia and major depressive disorder.
Trial Registration: ClinicalTrials.gov NCT00805454 December 9, 2008.