Abstract

Vatalanib (PTK787/ZK-222584) is a new oral antiangiogenic molecule that inhibits all known vascular endothelial growth factor receptors. Vatalanib is under investigation for the treatment of solid tumors. Disposition and biotransformation of vatalanib were studied in an open-label, single-center study in patients with advanced cancer. Seven patients were given a single oral ¹⁴C-radiolabeled dose of 1000 mg of vatalanib administered at steady state, obtained after 14 consecutive daily oral doses of 1000 mg of nonradiolabeled vatalanib. Plasma, urine, and feces were analyzed for radioactivity, vatalanib, and its metabolites. Metabolite patterns were determined by high-performance liquid chromatography coupled to radioactivity detection with off-line microplate solid scintillation counting and characterized by LC-MS. Vatalanib was well tolerated. The majority of adverse effects corresponded to common toxicity criteria grade 1 or 2. Two patients had stable disease for at least 7 months. Plasma C_max values of ¹⁴C radioactivity (38.3 ± 26.0 μM; mean ± S.D., n = 7) and vatalanib (15.8 ± 9.5 μM) were reached after 2 and 1.5 h (median), respectively, indicating rapid onset of absorption. Terminal elimination half-lives in plasma were 23.4 ± 5.5 h for ¹⁴C radioactivity and 4.6 ± 1.1 h for vatalanib. Vatalanib cleared mainly through oxidative metabolism. Two pharmacologically inactive metabolites, CGP-84368/ZK-260120 [(4-chlorophenyl)-[4-(1-oxy-pyridin-4-yl-methyl)-phthalazin-1-yl]-amine] and NVP-AAW378/ZK-261557 [rac-4-[(4-chloro-phenyl)amino]-α-(1-oxido-4-pyridyl)phthalazine-1-methanol], having systemic exposure comparable to that of vatalanib, contributed mainly to the total systemic exposure. Vatalanib and its metabolites were excreted rapidly and mainly via the biliary-fecal route. Excretion of radioactivity was largely complete, with a radiocarbon recovery between 67% and 96% of dose within 7 days (42–74% in feces, 13–29% in urine).