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Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity
Ist Teil von
Molecular cancer therapeutics, 2007-07, Vol.6 (7), p.2012-2021
Ort / Verlag
United States: American Association for Cancer Research
Erscheinungsjahr
2007
Link zum Volltext
Quelle
MEDLINE
Beschreibungen/Notizen
With the development of targeted therapeutics, especially for small-molecule inhibitors, it is important to understand whether
the observed in vivo efficacy correlates with the modulation of desired/intended target in vivo . We have developed a small-molecule inhibitor of all three vascular endothelial growth factor (VEGF) receptors (VEGFR), platelet-derived
growth factor receptor, and c-Kit tyrosine kinases, pazopanib (GW786034), which selectively inhibits VEGF-induced endothelial
cell proliferation. It has good oral exposure and inhibits angiogenesis and tumor growth in mice. Because bolus administration
of the compound results in large differences in C max and C trough , we investigated the effect of continuous infusion of a VEGFR inhibitor on tumor growth and angiogenesis. GW771806, which
has similar enzyme and cellular profiles to GW786034, was used for these studies due to higher solubility requirements for
infusion studies. Comparing the pharmacokinetics by two different routes of administration (bolus p.o. dosing and continuous
infusion), we showed that the antitumor and antiangiogenic activity of VEGFR inhibitors is dependent on steady-state concentration
of the compound above a threshold. The steady-state concentration required for these effects is consistent with the concentration
required for the inhibition of VEGF-induced VEGFR2 phosphorylation in mouse lungs. Furthermore, the steady-state concentration
of pazopanib determined from preclinical activity showed a strong correlation with the pharmacodynamic effects and antitumor
activity in the phase I clinical trial. [Mol Cancer Ther 2007;6(7):2012–21]