Chemistry Reference
In-Depth Information
100
90
80
70
1 mg
5 mg
10 mg
20 mg
60 mg
60
50
40
30
20
10
0
0
5
10
15
20
25
Time (h)
Figure 15.15
Mean projected a7 nAChR occupancies 0.5-24 h post-dose in humans
after a single oral dose of PHA-543613.
100
90
80
70
60
0
1
2
3
4
5
6
7
8
Day
Figure 15.16
Projected a7 nAChR occupancies at maximum (C
max
, filled symbols)
and minimum plasma concentrations (C
min
, unfilled symbols) of PHA-
543613 on day 1 and day 7 (steady-state) in humans after a twice-daily
oral dosing regimen of 6 (
B
), 21 (m), or 40 (
'
) mg.
to those in rats.
70
Furthermore, the SD data demonstrate a common obser-
vation for RO versus ligand concentration: the greatest changes in RO with the
smallest changes in ligand concentration occur within the 30-70% RO range,
whereas very small changes in RO occur with large changes in ligand con-
centration at RO
o
30% and 470%. In other words, increasing PHA-543613
C
p,max
6-fold (from 35 to 224 ngmL
1
for 10 and 60 mg, respectively) would
only increase maximal projected RO 1.1-fold (from 88% to 98%, respectively).
This phenomenon is also seen in the MD data in which increasing the dose from
6to40mgbid increases steady-state (i.e., day 7) C
p,max
7.5-fold and projected
RO only 1.1-fold. Importantly, from the RO data derived from the three MDs
tested, a7 nAChR occupancy is projected to have never fallen below 75% at
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