title: Evaluation of safety and tolerability, pharmacokinetics, and pharmacodynamics of BMS-820836 in healthy subjects: a placebo-controlled, ascending single-dose study.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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 [(11)C]DASB positron emission tomography (PET) after single-dose BMS-820836 (0.5 or 3 mg; n = 3 each) and DAT occupancy by applying [(11)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 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.
authors: Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb, Route 206 and Province Line Road, Lawrenceville, NJ, 08543-5400, USA.
authors: Robert
authors: R
authors: Risinger
authors: Zubin
authors: Z
authors: Bhagwagar
authors: Feng
authors: F
authors: Luo
authors: Matthew
authors: M
authors: Cahir
authors: Laura
authors: L
authors: Miler
authors: Anisha E
authors: AE
authors: Mendonza
authors: Jeffrey H
authors: JH
authors: Meyer
authors: Ming
authors: M
authors: Zheng
authors: Wendy
authors: W
authors: Hayes
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D001774:Blood Chemical Analysis; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007546:Isoquinolines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D014179:Neurotransmitter Uptake Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography; D011724:Pyridazines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D055815:Young Adult
chemical_list: C000594001:6-(2-methyl-4-(2-naphthyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)pyridazin-3-amine; D050483:Dopamine Plasma Membrane Transport Proteins; D007546:Isoquinolines; D014179:Neurotransmitter Uptake Inhibitors; D011724:Pyridazines; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins