Evaluation of safety and tolerability, pharmacokinetics, and pharmacodynamics of BMS-820836 in healthy subjects: a placebo-controlled, ascending single-dose study

BMS-820836, a novel triple monoamine reuptake inhibitor, is an experimental monotherapy for sufferers of major depressive disorder who have had an inadequate response to an existing antidepressant treatment. This study was conducted to evaluate the safety and tolerability, pharmacokinetics (PK), and serotonin transporter (SERT) and dopamine transporter (DAT) occupancy for single doses of BMS-820836 in healthy subjects. Healthy subjects were assigned to seven BMS-820836 dose panels (0.025, 0.1, 0.5, 1, 2, 3, and 5 mg; n = 8 each), in which subjects were randomly allocated 3:1 to a single BMS-820836 dose or matched placebo. Serial blood samples were collected on Days 1, 2, 3, 4, 7, and 14 to characterize the PK of BMS-820836. Following evaluation of the maximum tolerated dose, SERT occupancy was determined by applying [C-11]DASB positron emission tomography (PET) after single-dose BMS-820836 (0.5 or 3 mg; n = 3 each) and DAT occupancy by applying [C-11]PE2I PET after single-dose BMS-820836 (3 mg; n = 6). Single oral doses of BMS-820836 (0.025-3 mg) were generally safe and well tolerated. BMS-820836 had a median T (max) of 5.0-7.2 h and a mean apparent terminal T (1/2) of 34-57 h. Mean striatal SERT occupancies were 19 +/- 9 % and 82 +/- 8 % after single doses of 0.5 and 3 mg BMS-820836, respectively. The mean striatal DAT occupancy was 19 +/- 9 % after a single 3 mg BMS-820836 dose. Single doses of BMS-820836 have meaningful SERT and DAT occupancy and demonstrate an acceptable safety and tolerability profile in healthy control subjects.