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

• Published in: Psychopharmacology Vol. 232; no. 3; pp. 529 - 540
• Main Authors: Zheng, Ming, Appel, Lieuwe, Luo, Feng, Lane, Roger, Burt, David, Risinger, Robert, Antoni, Gunnar, Cahir, Matthew, Keswani, Sanjay, Hayes, Wendy, Bhagwagar, Zubin
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.02.2015; Springer; Springer Nature B.V
• Subjects: Adult; Antidepressants; Biomedical and Life Sciences; Biomedicine; Dopamine Plasma Membrane Transport Proteins - drug effects; Dosage and administration; Dose-Response Relationship, Drug; Double-Blind Method; Farmakokinetik och läkemedelsterapi; Female; Humans; Isoquinolines - administration & dosage; Isoquinolines - adverse effects; Isoquinolines - pharmacokinetics; Isoquinolines - pharmacology; Male; Middle Aged; Neostriatum - drug effects; Neurosciences; Neurotransmitter Uptake Inhibitors - administration & dosage; Neurotransmitter Uptake Inhibitors - adverse effects; Neurotransmitter Uptake Inhibitors - pharmacokinetics; Neurotransmitter Uptake Inhibitors - pharmacology; Original Investigation; Patient outcomes; Patient safety; PET; Pharmacokinetics; Pharmacokinetics and Drug Therapy; Pharmacological research; Pharmacology/Toxicology; Positron-Emission Tomography; Psychiatry; Psychopharmacology; Pyridazines - administration & dosage; Pyridazines - adverse effects; Pyridazines - pharmacokinetics; Pyridazines - pharmacology; reuptake inhibitors; Serotonin Plasma Membrane Transport Proteins - drug effects; Tomography; Young Adult; SERT; Triple monoamine reuptake inhibitor; DAT; Chronic treatment; Occupancy; Safety; Drug discovery; Pharmacokinetics; PET; BMS-820836
• ISSN: 0033-3158; 1432-2072; 1432-2072
• DOI: 10.1007/s00213-014-3688-x

Rationale 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.