Safety, pharmacokinetic, and positron emission tomography evaluation of serotonin and dopamine transporter occupancy following multiple-dose administration of the triple monoamine reuptake inhibitor BMS-820836.

Abstract

BMS-820836 is a novel antidepressant that selectively inhibits the reuptake of serotonin, norepinephrine, and dopamine. This Phase I study assessed safety, tolerability, and pharmacokinetics of multiple daily doses of BMS-820836 in healthy subjects. Central serotonin transporter (SERT) and dopamine transporter (DAT) occupancy were assessed using positron emission tomography and [(11)C]MADAM or [(11)C]PE2I, respectively. Fifty-seven healthy volunteers were enrolled in this double-blind, placebo-controlled, ascending multiple-dose study (ClincalTrials.gov identifier: NCT00892840). Eight participants in seven dose cohorts received oral doses of BMS-820836 (0.1-4mg) or placebo for 14days to assess safety, tolerability, and pharmacokinetics. Additionally, SERT and DAT occupancies were evaluated in 4-8 subjects per cohort at 8h post-dose on Day 10 and 24h post-dose on Day 15 at anticipated steady-state conditions. Most adverse events were mild to moderate; there were no serious safety concerns. Median maximum concentrations of BMS-820836 were observed at 4.0-5.5h post-dose; estimated elimination half-life was 44-74h. About 80% striatal SERT occupancy was achieved after multiple doses of 0.5mg BMS-820836 at both 8 and 24h post-dose. Striatal DAT occupancy ranged between 14% and 35% at 8h post-dose with a slight decline at 24h post-dose. Multiple daily doses of up to 4mg BMS-820836 appeared to be generally safe and well tolerated in a healthy population. SERT and DAT occupancies were in a range associated with therapeutic efficacy of antidepressants. Together with the pharmacokinetic profile of BMS-820836, the occupancy data support once-daily administration.