title: Improvement by solid dispersion of the bioavailability of KRN633, a selective inhibitor of VEGF receptor-2 tyrosine kinase, and identification of its potential therapeutic window.
abstract: 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.
authors.affiliation: CMC R&D Laboratories, Takasaki, Gunma, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Matsunaga
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Nakamura
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yamamoto
authors.forename: Eri
authors.initials: E
authors.lastname: Taguchi
authors.forename: Hiromi
authors.initials: H
authors.lastname: Tsunoda
authors.forename: Kazumi
authors.initials: K
authors.lastname: Takahashi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology; D001682:Biological Availability; D001808:Blood Vessels / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003460:Crystallization; D004339:Drug Compounding; D004355:Drug Stability; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology; D011799:Quinazolines / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D011799:Quinazolines; C508488:N-(2-chloro-4-((6,7-dimethoxy-4-quinazolinyl)oxy)phenyl)-N'-propylurea; D040301:Vascular Endothelial Growth Factor Receptor-2