Neurotransmitter transporter occupancy following administration of centanafadine sustained-release tablets: A phase 1 study in healthy male adults

Background: Centanafadine is an inhibitor of reuptake transporters for norepinephrine (NET), dopamine (DAT) and serotonin (SERT). Aims: This phase 1, adaptive-design positron emission tomography study investigated the occupancy time course of NET, DAT, and SERT and the relationship to centanafadine plasma concentrations. Methods: Healthy adult males received centanafadine sustained-release 400 mg/day for 4 days (N = 6) or 800 mg in a single day (N = 4). Assessments included safety monitoring; time course of occupancy of NET, DAT, and SERT; and centanafadine plasma concentrations. Results: Transporter occupancy was numerically higher for NET versus DAT or SERT. For NET, estimated (mean +/- standard error [SE]) maximal observable target occupancy (TOmax) and concentration at half maximal occupancy (IC50) were 64 +/- 7% and 132 +/- 65 ng/mL, respectively, for all regions and 82 +/- 13% and 135 +/- 97 ng/mL after excluding the thalamus, which showed high nonspecific binding. For DAT and SERT, TOmax could not be established and was assumed to be 100%; estimated IC50 (mean +/- SE) values were 1580 +/- 186 ng/mL and 1,760 +/- 309 ng/mL, respectively. For centanafadine, the estimated in vivo affinity ratio was 11.9 +/- 6.0 (mean +/- SE) for NET/DAT, 13.3 +/- 7.0 for NET/SERT, and 1.1 +/- 0.2 for DAT/SERT. DAT and SERT occupancies at a plasma concentration of 1400 ng/mL were estimated to be 47 and 44%, respectively. Conclusions: High occupancy at NET and moderate occupancy at DAT and SERT was observed at peak concentrations achieved following 400 mg total daily doses of centanafadine.

Automated summary

This study investigated the occupancy time course of NET, DAT, and SERT and their relationship to centanafadine plasma concentrations. The results showed high occupancy at NET and moderate occupancy at DAT and SERT following 400 mg total daily doses of centanafadine.