1. Evaluation of safety and tolerability, pharmacokinetics, and pharmacodynamics of BMS-820836 in healthy subjects: a placebo-controlled, ascending single-dose study.
- Author
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Risinger, Robert, Bhagwagar, Zubin, Luo, Feng, Cahir, Matthew, Miler, Laura, Mendonza, Anisha, Meyer, Jeffrey, Zheng, Ming, and Hayes, Wendy
- Subjects
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NEUROTRANSMITTER uptake inhibitors , *MONOAMINE oxidase inhibitors , *PSYCHOPHARMACOLOGICAL research , *PHARMACOKINETICS , *SEROTONIN transporters , *DOPAMINE uptake inhibitors , *DOPAMINERGIC mechanisms - 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 [C]DASB positron emission tomography (PET) after single-dose BMS-820836 (0.5 or 3 mg; n = 3 each) and DAT occupancy by applying [C]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 of 5.0-7.2 h and a mean apparent terminal T 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. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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