Abstract
Background
Based on in-vitro binding studies, SEP-432 is a triple monoamine reuptake inhibitor with a binding affinity for NE>5HT>DA. We determined the maximal tolerated dose (MTD) of SEP-432 to be 300mg/day, and in this study characterized its monoamine profile compared with duloxetine and placebo.
Methods
Eighteen healthy male and female subjects ages 18-50 were randomly assigned to receive either SEP-432 300mg/day (n=7), duloxetine 60mg/day (n=7) or placebo (n=4) for 14 days in a clinical research unit. CSF and plasma monoamines (NE, 5HT, and DA) and their primary metabolites (DHPG, 5HIAA, and DOPAC respectively) were quantified (by validated LC-MS-MS methods) over a 24-hour period following the last dose of study drug.
Results
Both SEP-432 and duloxetine significantly (p<0.05) decreased DHPG relative to placebo, with SEP-432 having a greater effect than duloxetine (39% and 28% decreases in CSF respectively). SEP-432 also had a statistically significant effect (p<0.05) on 5HT in plasma, with a trend to increase 5HT in CSF. No significant effects on DA or DOPAC were found with either drug. Changes in monoamines and metabolites over 24-hours and the pharmacokinetic profile of SEP-432 in CSF and plasma will also be described.
Discussion
At its MTD, SEP-432 showed significant monoamine biomarker effects consistent with a dual NE, 5HT reuptake inhibitor peripherally, but not centrally. The comparator duloxetine produced results indicating a central dual reuptake inhibitor mechanism, consistent with its clinical efficacy in pain and depression. This type of study provides mechanistic insights critical for decision-making in early clinical development.
