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

Abstract

Rationale: 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. Objectives: 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. Methods: 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 [11C]DASB positron emission tomography (PET) after single-dose BMS-820836 (0.5 or 3 mg; n=3 each) and DAT occupancy by applying [11C]PE2I PET after single-dose BMS-820836 (3 mg; n=6). Results: 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. Conclusions: Single doses of BMS-820836 have meaningful SERT and DAT occupancy and demonstrate an acceptable safety and tolerability profile in healthy control subjects. © 2013 Springer-Verlag Berlin Heidelberg.