Frankel, 2018 An open-label positron emission tomography study to evaluate serotonin transporter occupancy following escalating dosing regimens of (R)-(-)-O-desmethylvenlafaxine and racemic O-desmethylvenlafaxine.

[Andie]

Frankle WG, et al. Synapse. 2018

An open-label positron emission tomography study to evaluate serotonin transporter occupancy following escalating dosing regimens of (R)-(-)-O-desmethylvenlafaxine and racemic O-desmethylvenlafaxine.

Authors

Frankle WG¹, Robertson B², Maier G³, Paris J⁴, Asmonga D⁴, May M⁴, Himes ML⁴, Mason NS⁵, Mathis CA⁵, Narendran R^4,5.

Author information

1

Department of Psychiatry, NYU Langone Medical Center, New York, New York.

2

Shire Pharmaceuticals Inc., Lexington, Massachusetts.

3

MaierMetrics and Associates, LLC, Boston, Massachusetts.

4

Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania.

5

Department of Radiology, University of Pittsburgh, Pittsburgh, Pennsylvania.

Citation

Synapse. 2018 Mar;72(3). doi: 10.1002/syn.22021. Epub 2017 Dec 13.

 

Links 

https://www.ncbi.nlm.nih.gov/pubmed/29216407.

Full text available here (requires membership) https://onlinelibrary.wiley.com/doi/abs/10.1002/syn.22021

 

Abstract

SEP-227162 [R(-)-O-desmethylvenlafaxine] is an enantiomer of the venlafaxine metabolite O-desmethylvenlafaxine (ODV, Pristiq™, Wyeth). This study compared the serotonin transporter (SERT) occupancy achieved by SEP-227162 and ODV, at daily doses of 25, 50, 100, and 150 mg using [11 C]DASB positron emission tomography (PET). Sixteen healthy male subjects participated in one of four dose groups (N = 4 per group) during which they were administered two doses of the study drug (SEP-227162 or ODV). For each study drug, total daily doses of 25, 50, 100, and150 mg were studied. Subjects underwent three PET scans with [11 C]DASB. A baseline, off-medication, scan was performed prior to dosing and a [11 C]DASB PET scan was performed after 72 hr at each dose level. [11 C]DASB binding potential (BPND ) was calculated using the simplified reference tissue method. SERT occupancy was calculated as the change in BPND (ΔBPND ) from baseline scan to the on-medication scan relative to the baseline BPND value. SEP-227162 and ODV significantly reduced regional distribution volumes and region BPND values in a dose-dependent manner. Across all doses ODV produced significantly greater SERT occupancy than SEP-227162 (ANOVA F = 21.8, df = 1,23, p < .001). The total daily dose required to provide 50% SERT occupancy was 24.8 mg for SEP-227162 and 14.4 mg for ODV. In vitro data suggests a ratio of 3.3:1 for binding at human SERT for SEP-227162 relative to ODV. Our study suggests a ratio of 1.7:1, highlighting the value of in vivo imaging in the drug development process.

PMID

 29216407 [Indexed for MEDLINE].

Edited January 5, 2019 by Altostrata
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[Andie]

Here is the graph 

 

https://onlinelibrary.wiley.com/toc/10982396/72/3

[Altostrata]

That is a very familiar slope! Why taper? SERT transporter occupancy studies show importance of gradual change in plasma concentration

 

Thanks, Andie.