An open-label, positron emission tomography study of the striatal D₂/D₃ 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 D₂/D₃ 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 D₂/D₃ receptor antagonist [¹¹C]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 D₂/D₃ 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 (EC₅₀) 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 D₂/D₃ 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.