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An open‐label positron emission tomography study to evaluate serotonin transporter occupancy following escalating dosing regimens of ( R )‐(–)‐ O ‐desmethylvenlafaxine and racemic O ‐desmethylvenlafaxine
Author(s) -
Frankle W. Gordon,
Robertson Brigitte,
Maier Gary,
Paris Jennifer,
Asmonga Deanna,
May Maureen,
Himes Michael L.,
Mason N. Scott,
Mathis Chester A.,
Narendran Rajesh
Publication year - 2018
Publication title -
synapse
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.809
H-Index - 106
eISSN - 1098-2396
pISSN - 0887-4476
DOI - 10.1002/syn.22021
Subject(s) - serotonin transporter , positron emission tomography , dosing , nuclear medicine , medicine , standardized uptake value , pharmacology , serotonin , receptor
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 (BP ND ) was calculated using the simplified reference tissue method. SERT occupancy was calculated as the change in BP ND (ΔBP ND ) from baseline scan to the on‐medication scan relative to the baseline BP ND value. SEP‐227162 and ODV significantly reduced regional distribution volumes and region BP ND 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.