A study with a partial subtype selective GABAA α2,3 agonist, using
quantitative pharmacodynamic measurements in healthy subjects
Poster copy
Chen, X1,2 , Jaeger, J 3*, Lappalainen, J 4, Maruff, P 3, Smith, MA 5*, Cross, AJ4, van Gerven, JMA2
1Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Beijing, China; 2Centre for Human Drug Research ,Leiden, The Netherlands;
3Cogstate, Melbourne Australia and New Haven CT, USA;4AstraZeneca, R&D, Wilmington Delaware and Cambridge MA; 5Shire Pharmaceuticals, PA, USA
AIM
To investigate the effects of AZD7325 on cognitive, visuomotor, neurophysiological and postural stability measures
relative to lorazepam at doses that result in comparable
or higher occupancy.
■
The slopes of the regression lines were flatter for
AZD7325, particularly for the ΔLog(Sway)-ΔSPV
relation and the ΔVASalertness-ΔSPV relation, compared
to lorazepam (Figure 2).
2.86
■ Design: single-dose, randomized, double-blind,
4-way crossover study in 16 healthy men
■ Treatments: AZD7325
10mg, AZD7325 2 mg,
Lorazepam 2 mg, Placebo
Identification
2.82
2.80
2.78
2.76
2.74
2.72
2.70
2.68
2.66
2.64
-2
-1
0
1
2
3
4
5
6
7
8
9
Detection, Identification, Chase
test
Visual and Verbal Learning
International Shopping List (ISL), One
Card Learning
Long term memory
ISL delayed recall
Executive function
Groton Maze
group mean (SE) prop correct (arcsine)
hours
CogState test
1.00
0.95
0.90
0.85
0.80
0.75
0.70
0.65
0.60
0.55
0.50
0.45
0.40
-3
ΔSPV
90.00
low
high
loraz
placebo
Visual Learning
-2
-1
0
1
2
3
4
hours
5
6
7
8
9
low
high
loraz
placebo
80.00
70.00
60.00
40.00
30.00
20.00
Executive Functioning
10.00
0.00
-3
-2
-1
0
1
2
3
hours
4
5
6
7
8
■
■
■
scales,
9
ΔSPV
Figure 2.:ΔSPV-ΔVASalertness and ΔSPV-Δlog(Sway) relation
■
50.00
CONCLUSIONS
■ The characteristic ΔSPV-relative effect profiles of
AZD7325 vs. lorazepam suggests anxio-selectivity
related to α2,3-selective GABAA agonism. However,
exploration of higher doses may be warranted.
■ The lack of effects on most CNS-PD parameters
■ CNS-PD test battery:
■ Neurophysiological function: saccadic peak velocity
(SPV), smooth pursuit
Postural balance: Body sway
Eye-hand coordination: Adaptive tracking
Subjective effect: Visual analogue
VASalertness
AZD7325 10 mg
low
high
loraz
placebo
2.84
-3
■CogState battery:
Attention, processing speed,
visuo-motor coordination
Neither dose of AZD7325 affected VASalertness, SPV,
sway, smooth pursuit, tracking, or any cognitive
measures (Figure 1), which were all robustly impaired
by lorazepam 2mg (all p<0.05).
■
METHODS
Cognitive function
AZD7325 2 mg
group mean (SE) Errors)
■
■
RESULTS
ΔVAS alertness
Does AZD7325, a novel α2,3-subtype selective GABAA
modulator produce a benzodiazepine-like profile on
cognition and neurophysiologic biomarkers at doses that
result in high GABAA receptor occupancy?
■
Δlog(Sway)
INTRODUCTION
group mean (SE) speed (log10RT)
■
suggests lower cognitive and neurophysiological
side-effect burden than non-selective benzodiazepines.
Figure 1:Group mean (+SE) performance on CogState
measures at each of the time points. Note: Detection and
Chase test profiles were very similar to that observed on
Identification task, shown above.
The authors report no conflicts of interest for this work
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