Exploratory Biomarker Study of the Triple Reuptake Inhibitor SEP-432 Compared to the Dual Reuptake Inhibitor Duloxetine in Healthy Normal Subjects

Abstract

Introduction: SEP-432 is a triple monoamine reuptake inhibitor of norepinephrine (NE), serotonin (5-HT), and dopamine (DA), based on in vitro binding studies. We sought evidence that SEP-432 engages these monoamine systems by measuring concentrations of monoamines and/or their main metabolites in cerebrospinal fluid (CSF) and plasma and comparing results to duloxetine, a dual reuptake inhibitor of NE and 5-HT.

Methods: Eighteen healthy normal subjects received either SEP-432 (300 mg/day), duloxetine (60 mg/day), or placebo for 14 days in-clinic (double blind) with CSF and plasma collections at baseline (single lumbar puncture) and Day 14 (24-h CSF and plasma collection). Concentrations of monoamines and their metabolites, as well as pharmacokinetic concentrations of SEP-432 and metabolite, were quantified by liquid chromatography-tandem mass spectrometry.

Results: Compared to placebo in the Day 14 area under the curve 24-h (AUC0-24 h ) analysis, SEP-432 significantly (P < 0.05) decreased the NE metabolite dihydroxyphenylglycol (DHPG) in CSF and plasma, decreased 5-HT in plasma, and did not affect DA metabolites, while duloxetine had significant effects on DHPG and 5-HT. Time-matched baseline to Day 14 biomarker comparisons confirmed these findings.

Conclusion: CSF monoamine biomarkers confirmed central NET activity for SEP-432 and duloxetine's dual reuptake inhibition.

Keywords: Biomarkers; Cerebrospinal fluid; Duloxetine; Monoamine reuptake inhibitor; SEP-432.

Figure 1

Average Values of Hourly DHPG Concentration in CSF, Comparing Day 1 (Predose Baseline) to Day 14 (the 0–24 Hour Time Points) after Treatment with Placebo, Duloxetine (60 mg), or SEP‐432 (300 mg).

Figure 2

Average Values of Hourly 5‐HT Concentrations in CSF, Comparing Day 1 (Predose Baseline) to Day 14 (the 0–24 Hour Time Points) after Treatment with Duloxetine (60 mg), SEP 432 (300 mg), and Placebo (n.s., nonsignificant).

Figure 3

Mean Values for SEP‐432 Plasma and CSF Concentrations over 24 h (Day 14) after 300 mg Dosing to Steady State (note that the SEP‐432 concentrations are displayed on a log10 scale; error bars indicate SEM).