An open-label, positron emission tomography study of the striatal D2/D3 receptor occupancy and pharmacokinetics of single-dose oral brexpiprazole in healthy participants
| Autor: | Arash Raoufinia, Dean F. Wong, James Robert Brašić, Robert A. Forbes, Robert D. McQuade, Hiroto Kuwabara, Tetsuro Kikuchi, Patricia Bricmont |
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| Rok vydání: | 2020 |
| Předmět: |
Target engagement
Adult Male Antipsychotic agents Metabolic Clearance Rate Caudate nucleus Cmax Thiophenes Quinolones Pharmacology Receptors Dopamine 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Pharmacokinetics Dopamine receptor D3 Dose determination medicine Humans Pharmacology (medical) Dopamine receptors Brexpiprazole Raclopride Dose-Response Relationship Drug business.industry Putamen Correction General Medicine Pharmacokinetics and Disposition Corpus Striatum 030227 psychiatry chemistry Tolerability Area Under Curve Positron-Emission Tomography Dopamine Agonists Female business Receptor occupancy 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | European Journal of Clinical Pharmacology |
| ISSN: | 1432-1041 0031-6970 |
| DOI: | 10.1007/s00228-020-03021-9 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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