Chemistry Reference
In-Depth Information
Tier 1
in vitro
screens:
hSRI; hNRI; hDRI
clog
P
; Log D
7.4
; HLM; CYP2D6-i;
hERG (binding); CaCO-2; MDCK-mdr1
Tier 2
in vitro
screens:
CYP inhibition and metabolism
RLM; DLM; BIOPRINT
TM
SRI and NRI (rat and dog)
Tier 3
in vivo
screens:
i.v. and p.o. PK (rat then dog)
CSF levels (rat)
microdialysis (rat)
Tier 4
in vivo
screens:
model of urethral tone (dog)
Figure 12.2
Project screening sequence.
each series (Figure 12.2). In the canine model of SUI, test compounds were
administered by i.v. infusion to anaesthetized female dogs and a pressure
transducer inserted into the urethra as far as the bladder neck. The transducer
would then be slowly withdrawn whilst recording the pressure, and a mea-
surement of peak urethral pressure (PUP) would be taken: the percentage
difference in PUP over vehicle was plotted against steady-state free plasma
concentrations of drug. The percentage increase in PUP was used as a measure
of e
cacy of the drug in improving urethral tone. This model could also be
used for a preliminary measurement of cardiovascular safety data such as mean
arterial pressure (MAP) and heart rate (HR).
Evaluation of duloxetine in this model showed a drug-related, dose-depen-
dent increase in (PUP) with a maximal increase of 35% at free plasma levels of
r
15 nM (n
ΒΌ
5) (Figure 12.3). An increase of 26% in PUP was observed at a
free plasma concentration of 4 nM, which we believed to be close to the free
plasma levels from a therapeutic dose of duloxetine for SUI (40mg bid). The
increase in PUP was also accompanied by a small dose-dependent increase in
MAP relative to control, which is consistent with the clinical findings.
25
Evo-
lution of the methodology of this model by means of the application in con-
scious dogs was thought to translate through to the clinical setting and allow a
direct comparison of ecacy between dog, healthy volunteers and patients, i.e.
we felt the model would serve as a translatable clinical biomarker.
27
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