An open-label, positron emission tomography study of the striatal D 2 /D 3 receptor occupancy and pharmacokinetics of si
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PHARMACOKINETICS AND DISPOSITION
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 1,3 & Arash Raoufinia 2 & Patricia Bricmont 2 & James R. Brašić 3 & Robert D. McQuade 2 & Robert A. Forbes 2 & Tetsuro Kikuchi 4 & Hiroto Kuwabara 3 Received: 26 May 2020 / Accepted: 14 October 2020 # The Author(s) 2020
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
Introduction Brexpiprazole (7-{4-[4-(1-benzothiophen-4-yl)piperazin-1yl]butoxy}quinolin-2(1H)-one; chemical structure shown in
Fig. S1 in the Online Resource) is a serotonin–dopamine activity modulator that acts as a partial agonist at serotonin 5-HT1A (Ki = 0.12 nM) and dopamine D2 (Ki = 0.30 nM) receptors, and as an antagonist at serotonin 5-HT2A (Ki =
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00228-020-03021-9) contains supplementary material, which is available to authorized users. * Dean F. Wong [email protected]; [email protected] 1
Lab of CNS Neuropsychopharmacology And Multimodal Imaging (CNAMI), Mallinckrodt Institute of Radiology, Washington University, 4525 Scott Avenue Suite 3114, St. Louis, MO 63110, USA
2
Otsuka Pharmaceutical
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