title: 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: BACKGROUND
  BMS-820836 is a novel antidepressant that selectively inhibits the reuptake of serotonin, norepinephrine, and dopamine.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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 (0.1-4 mg) or placebo for 14 days to assess safety, tolerability, and pharmacokinetics. Additionally, SERT and DAT occupancies were evaluated in 4-8 subjects per cohort at 8 h post-dose on Day 10 and 24 h post-dose on Day 15 at anticipated steady-state conditions.
  
  
  RESULTS
  Most adverse events were mild to moderate; there were no serious safety concerns. Median maximum concentrations of BMS-820836 were observed at 4.0-5.5 h post-dose; estimated elimination half-life was 44-74 h. About 80 % striatal SERT occupancy was achieved after multiple doses of 0.5 mg BMS-820836 at both 8 and 24 h post-dose. Striatal DAT occupancy ranged between 14 % and 35 % at 8 h post-dose with a slight decline at 24 h post-dose.
  
  
  CONCLUSIONS
  Multiple daily doses of up to 4 mg 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.
authors.affiliation: Exploratory Clinical and Translational Research, Bristol-Myers Squibb, Princeton, NJ, 08534, USA, Ming.Zheng@bms.com.
authors.forename: Ming
authors.initials: M
authors.lastname: Zheng
authors.forename: Lieuwe
authors.initials: L
authors.lastname: Appel
authors.forename: Feng
authors.initials: F
authors.lastname: Luo
authors.forename: Roger
authors.initials: R
authors.lastname: Lane
authors.forename: David
authors.initials: D
authors.lastname: Burt
authors.forename: Robert
authors.initials: R
authors.lastname: Risinger
authors.forename: Gunnar
authors.initials: G
authors.lastname: Antoni
authors.forename: Matthew
authors.initials: M
authors.lastname: Cahir
authors.forename: Sanjay
authors.initials: S
authors.lastname: Keswani
authors.forename: Wendy
authors.initials: W
authors.lastname: Hayes
authors.forename: Zubin
authors.initials: Z
authors.lastname: Bhagwagar
mesh_terms: D000328:Adult; D050483:Dopamine Plasma Membrane Transport Proteins / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007546:Isoquinolines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D017072:Neostriatum / Q000187:drug effects*; D014179:Neurotransmitter Uptake Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D049268:Positron-Emission Tomography; D011724:Pyridazines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000187:drug effects*; 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