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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00228-020-03021-9) contains supplementary material, which is available to authorized users.