Atomoxetine (Strattera) is a highly selective norepinephrine transporter (NET) antagonist that is indicated for the treatment of attention deficit disorders. The purpose of this study was to establish the NET occupancy-plasma atomoxetine relationships for healthy adults and identify minimal doses that produce the maximal occupancy.
Methods
Ten volunteers (33 ± 3 years; 9 M, 1F) participated with Group 1 (n=3) receiving 40 to 160 mg daily. PET scans were acquired at baseline and 12 hours after the last dose on days 11, 18, and 19. Group 2 (n=7) was treated with 20 to 160 mg daily with scans at baseline and at 3 time-points after the last dose on day 10. Each 90-minute PET utilized high specific activity (19 ± 2 Ci/micromole) 11C MeNER with average activity (19 ± 0.2 mCi) and mass (0.5 ± 0.04 micrograms). Subjects had radial arterial input (first two scans-group 1, all scans-group 2). Volumes of interest (VOIs) were defined for the thalamus, putamen, caudate nucleus, pons, and cerebellum on SPGR MRI. Binding potential (BP) was estimated with four approaches: Linear version of simplified reference tissue method using (1) white matter (LSRTM-WM) and (2) the caudate (LSRTM-CN), (3) one-tissue compartmental models with arterial input (1C-art) and (4) arterial input hyperplot (art-HP), with the latter two techniques using an inhibition plot method to estimate distribution volume1, 2 The percent occupancy was obtained by calculating the reduction in BP during the on-drug conditions. The Michaelis Menten equation (NET-OCC=Omax [atomox] p/(k+ [atomox] p)) where Omax is the maximal occupancy and [atomox] p is the plasma atomoxetine.
Results
The kinetics of the radiotracer was found to be relatively slow peaking at about 70 to 90 minutes after injection. The brain injected dose peaked at slightly more than 2%. Plasma atomoxetine ranged from 0.25 to 1329 ng/ml. The Omax for the thalamus, a typical region, were 34% (LSRTM-WM), 59.7% (LSRTM-CN), 61.5 (1C-art), and 48.0% (Art-HP) Eighty percent of Omax was achieved in all subjects who had a daily 80 mg dose for 10 days. Plasma atomoxetine decreased sharply after the last dose in post-discontinuation scans, consistent with its known plasma half-life.
Conclusions
The results illustrate the feasibility of measuring NET blockade with MeNER. However, its slow kinetics, relatively low target-to-background levels, and the apparent absence of an ideal reference region in humans, create uncertainty about the absolute occupancy. The inability to show complete saturation at supra-therapeutic doses might reflect non-competitive inhibition between the radiotracer and the inhibitor. However, the dose occupancy curves were similar with all 4 methods, confirm the apparent saturation at multiple plasma levels, and demonstrate the principle of NET occupancy as an aid for future NET drug development.