An open-label, positron emission tomography study of the striatal D/D 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/D 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/D receptor antagonist [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/D 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) were 89.2% for the putamen and 95.4% for the caudate nucleus; plasma concentrations predicted to provide 50% of O (EC) were 8.13 ng/mL and 7.75 ng/mL, respectively. Brexpiprazole area under the concentration-time curve (AUC) and maximum plasma concentration (C) 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/D 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.