uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
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
Show others and affiliations
2015 (English)In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 232, no 3, 529-540 p.Article in journal (Refereed) Published
Abstract [en]

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 [11C]MADAM or [11C]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.

Place, publisher, year, edition, pages
Springer Publishing Company, 2015. Vol. 232, no 3, 529-540 p.
Keyword [en]
PET, reuptake inhibitors
National Category
Pharmaceutical Sciences Pharmacology and Toxicology Psychiatry
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
URN: urn:nbn:se:uu:diva-240985DOI: 10.1007/s00213-014-3688-xISI: 000348307000005OAI: oai:DiVA.org:uu-240985DiVA: diva2:777476
Available from: 2015-01-08 Created: 2015-01-08 Last updated: 2017-12-05Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full text

Authority records BETA

Antoni, Gunnar

Search in DiVA

By author/editor
Antoni, Gunnar
By organisation
Preclinical PET Platform
In the same journal
Psychopharmacology
Pharmaceutical SciencesPharmacology and ToxicologyPsychiatry

Search outside of DiVA

GoogleGoogle Scholar

doi
urn-nbn

Altmetric score

doi
urn-nbn
Total: 504 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf