Chemistry Reference
In-Depth Information
Figure 4.11
Inhibition of the phosphorylation of both IR and IGF-1R in colorectal
tumor cells HT-29 and Colo205 by OSI-906 (signal realized by capture
array).
Table 4.16 Median pharmacokinetic parameters for OSI-906 following iv and
oral administration in different species.
a
iv
Species
Mouse (F)
Rat (F)
Dog (M)
Dose (mg kg
1
)
5
5
2.5
Elimination t
1/2
(h)
2.14
2.64
1.18
V
ss
(L kg
1
)
2.05
0.79
4.30
Cl (mLmin
1
kg
1
)
12
4
39
AUC
0
N
(ng hmL
1
)
6954
23123
1066
Oral
Species Mouse (F) Rat (F) Dog (M)
Dose (mg kg
1
) 5 25 75 250 12.5 100 5
C
max
(mM) 3.42 16.04
b
16.80
c
41.99 10.01 34.64 1.20
AUC
0
last
(ng hmL
1
) 6770 26741 87455 317487 42832 424076 1328
%F 98 100 84 4100 74 92 64
a
Cl
¼
clearance, V
ss
¼
volume of distribution at steady state, t
1/2
¼
elimination half-life, and AUC
0-
N
¼
area under the concentration-time curve extrapolated to infinity. C
max
¼
maximum measured
plasma concentration, C
24h
¼
plasma concentration at 24 h, and AUC
0
last
¼
area under the con-
centration-time curve extrapolated to the last measured sampling time. The dose vehicle was
25mM tartaric acid, except for the 5mg kg
1
dose in the mouse where saline pH2 was used.
b
C
24h
¼
0.02 mM.
c
C
24h
¼
2.92 mM.
highlighting the difference in PK properties when comparing molecules with
basic substituents versus a neutral alcohol in this series. The PK parameters
following oral administration have been evaluated in the female CD-1 mouse,
female Sprague Dawley rat, and the male beagle dog (Table 4.16) and were
subsequently used for an allometric extrapolation to humans (data not shown);
in each species, the oral bioavailability is high. In the mouse, the AUC
0-last
and
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