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

• Published in: Psychopharmacology Vol. 231; no. 11; pp. 2299 - 2310
• Main Authors: Risinger, Robert, Bhagwagar, Zubin, Luo, Feng, Cahir, Matthew, Miler, Laura, Mendonza, Anisha E., Meyer, Jeffrey H., Zheng, Ming, Hayes, Wendy
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.06.2014; Springer; Springer Nature B.V
• Subjects: Administration, Oral; Adolescent; Adult; Antidepressants; Biomedical and Life Sciences; Biomedicine; Blood Chemical Analysis; Brain - diagnostic imaging; Brain - drug effects; Brain - metabolism; Complications and side effects; Dopamine Plasma Membrane Transport Proteins - metabolism; Dosage and administration; Dose-Response Relationship, Drug; Double-Blind Method; Drug therapy; Female; Health; Humans; Isoquinolines - administration & dosage; Isoquinolines - adverse effects; Isoquinolines - pharmacokinetics; Kinetics; Major depressive disorder; Male; Maximum Tolerated Dose; Middle Aged; Neurosciences; Neurotransmitter Uptake Inhibitors - administration & dosage; Neurotransmitter Uptake Inhibitors - adverse effects; Neurotransmitter Uptake Inhibitors - pharmacokinetics; Original Investigation; Pharmacokinetics; Pharmacology; Pharmacology/Toxicology; Placebo effect; Positron-Emission Tomography; Psychiatry; Pyridazines - administration & dosage; Pyridazines - adverse effects; Pyridazines - pharmacokinetics; Serotonin Plasma Membrane Transport Proteins - metabolism; Young Adult; United States; Pharmacodynamics; Phase I; Triple monoamine reuptake inhibitor; Occupancy; Single dose; Tolerability; Safety; Pharmacokinetics; Positron emission tomography; BMS-820836
• ISSN: 0033-3158; 1432-2072; 1432-2072
• DOI: 10.1007/s00213-013-3391-3

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 [ 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.