KRN633 is a potent inhibitor of
vascular endothelial growth factor (
VEGF) receptor tyrosine kinases. However, it is poorly water-soluble; consequently, relatively high doses are required to achieve substantial in vivo
tumor growth suppression after
oral administration. We subjected
KRN633 to the solid dispersion technique to improve its solubility, absorption, and antitumor efficacy after
oral administration. This technique transformed the
drug into an amorphous state and dramatically improved its dissolution rate. It also enhanced the bioavailability of the
drug in rats by approximately 7.5-fold. The solid dispersion form of
KRN633 also dramatically inhibited human
tumor growth in murine and rat xenograft models: similar rates of
tumor growth inhibition were obtained with 10- to 25-fold lower doses of the solid dispersion preparation relative to the pure
drug in its crystalline state. Histologic analysis of
tumors treated with the solid dispersion preparation revealed a significant reduction in microvessel density at much lower doses when compared with the crystalline form preparation. In addition, a dose-finding study using the solid dispersion form in a rat xenograft model revealed that there was a substantial range of doses at which
KRN633 in the solid dispersion form showed significant antitumor activity but did not induce
weight loss or elevate total urinary
protein levels. These data suggest that the solid dispersion technique is an effective approach for developing
KRN633 drug products and that
KRN633 in the solid dispersion form may be a highly potent, orally available
drug with a wide therapeutic window for diseases associated with abnormal angiogenesis.