The Discovery of OSI-906, a Small-molecule Inhibitor of the Insulin-like Growth Factor-1 and Insulin Receptors - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 96

C max are approximately linear between 5 and 250mg kg 1 ; however, the C max is
not dose proportional. This lack of C max dose-proportionality is speculated to
be due to dissolution rate-limited absorption at the higher doses. Consequently,
at higher doses, the plasma concentration at 24 h is disproportionately higher.
Similarly in the rat, the AUC 0-last is approximately linear between 12.5 and
100mg kg 1 , while the C max is not dose-proportional in this range. Upon
subchronic dosing in mice in TGI studies, it is interesting to note that while the
C max values for the 25 and 75mg kg 1 doses are very similar at 16.04 and
16.80 mM, respectively, the AUC and C 24h values at the 75mg kg 1 dose are
approximately 2.5- and 146-fold higher, respectively.

4.12 OSI-906: Antitumor Effects
OSI-906 was evaluated first for in vivo ecacy in TGI studies in the LISN
xenograft model. 39 In this study, OSI-906 was dosed orally at 25 and 75mg
kg 1 once per day over 12 days. There was a dose-dependent effect on tumor
growth inhibition, with the 75mg kg 1 dose resulting in 100% TGI and 55%
regression, while the 25mg kg 1 dose afforded marginal TGI of 60% with no
regression (Figure 4.12). Both doses showed statistically significant anti-tumor
effects with p o 0.001 vs. control treated animals. There was o 10% body weight
loss (BWL) with the animals treated with the 25mg kg 1 dose and an average of
16% BWL with the 75mg kg 1 group in this study. OSI-906 was profiled in
other xenograft models, including the GEO colorectal and Colo-205 lines
where it displayed significant TGI (Z90%) when dosed orally at 60mg kg 1
once-a-day for 14 days (data not shown). 42,43 In the GEO study, the mice were

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Figure 4.12 Antitumor activity of orally dosed OSI-906 in the LISN xenograft model.