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evaluated for hyperglycemia (data not shown) and transient hyperglycemia was
noted at the end of the 14-day dosing period for the first 8 h, with glucose levels
returning to normal by 24 h.
4.13 OSI-906: Pharmacokinetic/Pharmacodynamic
Correlation
To assess the drug exposure required for inhibition of tumor IGF-1R in vivo,a
PD experiment was performed in LISN tumors in which the relationship
between inhibition of IGF-1R phosphorylation (PD) and drug exposure (PK)
was evaluated (Figure 4.13).
39
Dose escalating studies revealed that maximal
inhibition of IGF-1R phosphorylation (80%) by OSI-906 at 75mg kg
1
was
achieved between 4-24 h, with plasma drug concentrations of 26.6 and 4.77 mM
at the 4 and 24 h timepoints, respectively. The continued target inhibition at
24 h correlated with plasma drug exposures at 24 h being greater than the IGF-
1R cell
þ
mouse plasma (mP) IC
50
of 1.28 mM. The lower dose of 25mg kg
1
provided initial target coverage from 4 to 16 h, but failed to provide adequate
IGF-1R coverage out to 24 h (data not shown), paralleling the aforementioned
PK profile where the C
24h
for the 25mg kg
1
dose is 64-fold below the cell
þ
mP
IC
50
. Thus maximal inhibition of IGF-1R phosphorylation, maintained for at
least a full 24 h with OSI-906 at 75mg kg
1
, as shown in Figure 4.13, is con-
sistent with the robust anti-tumor activity observed in the LISN xenograft
model. These observations, together with the substantially greater TGI
observed with 75mg kg
1
relative to 25mg kg
1
, suggest that maximal anti-
tumor ecacy in this model requires maintenance of plasma levels sucient to
chronically suppress IGF-1R phosphorylation in tumors. A similar PK/PD
correlation was observed in the GEO and Colo-205 xenograft studies. Such a
correlation, in conjunction with the IGF-1R and IR cell
þ
human plasma IC
50
p-IGF-1R
plasma [OSI-906]
150
30
100
20
50
10
0
0
0
8
16
24
Time after dosing (hr)
Figure 4.13
Pharmacokinetic/pharmacodynamic relationship of 75mg kg
1
orally
dosed OSI-906 in the LISN tumor xenograft model.
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