An open-label, positron emission tomography study of the striatal D2/D3 receptor occupancy and pharmacokinetics of single-dose oral brexpiprazole in healthy participants

Dean F Wong, Arash Raoufinia, Patricia Bricmont, James R Brašić, Robert D McQuade, Robert A Forbes, Tetsuro Kikuchi, Hiroto Kuwabara, Dean F Wong, Arash Raoufinia, Patricia Bricmont, James R Brašić, Robert D McQuade, Robert A Forbes, Tetsuro Kikuchi, Hiroto Kuwabara

Abstract

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 (Omax) were 89.2% for the putamen and 95.4% for the caudate nucleus; plasma concentrations predicted to provide 50% of Omax (EC50) were 8.13 ng/mL and 7.75 ng/mL, respectively. Brexpiprazole area under the concentration-time curve (AUC∞) and maximum plasma concentration (Cmax) 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.

Keywords: Antipsychotic agents; Brexpiprazole; Dopamine receptors; Dose determination; Positron-emission tomography; Raclopride; Receptor occupancy; Target engagement.

Conflict of interest statement

Dean F. Wong received a contract to Johns Hopkins University from Otsuka during this study and has received contracts to Johns Hopkins University from Lilly/Avid, Lundbeck (Denmark/US), Intracellular Technologies NYC, and Roche Neuroscience, and from LB Pharma to Washington University. Arash Raoufinia, Patricia Bricmont, Robert D. McQuade and Robert A. Forbes are full-time employees of Otsuka Pharmaceutical Development & Commercialization Inc. James R. Brašić and Hiroto Kuwabara declare no conflict of interest. Tetsuro Kikuchi is a full-time employee of Otsuka Pharmaceutical Co., Ltd.

Figures

Fig. 1
Fig. 1
Mean trans-axial a MRI (n = 13) and b–d PET BPND images with [11C]raclopride, at a level showing the putamen and caudate nucleus. Panel b shows mean BPND at baseline (n = 13). Panel c shows mean BPND for arbitrarily selected ‘low’ brexpiprazole plasma concentration (< 20 ng/mL; n = 13). Panel d shows mean BPND for arbitrarily selected ‘high’ brexpiprazole plasma concentration (> 20 ng/mL; n = 12). BPND binding potential relative to non-displaceable binding, C caudate nucleus, MRI magnetic resonance imaging, P putamen, PET positron emission tomography
Fig. 2
Fig. 2
Mean dopamine D2/D3 receptor occupancy at 4 h and 23.5 h following a single oral dose of brexpiprazole (n = 2 per dose group except where there is no error bar, n = 1), as a function of dose. Error bars represent standard deviation
Fig. 3
Fig. 3
Dopamine D2/D3 receptor occupancy versus brexpiprazole plasma concentration a following a single oral dose (n = 12), and b extrapolated to expected multiple-dose concentrations. The mean plasma concentration across four time points spanning the duration of PET data acquisition was used for each data point. Omax maximum obtainable receptor occupancy, PET positron emission tomography
Fig. 4
Fig. 4
Mean a brexpiprazole and b its main metabolite, DM-3411, plasma concentration over time following a single oral dose of brexpiprazole (n = 2 per dose group)

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