ABSTRACT
The disposition and metabolism of a Chk-1 inhibitor (LY2603618) was characterized following a 1-h intravenous administration of a single 250-mg dose of [14C]LY2603618 (50 µCi) to patients with advanced or metastatic solid tumors. LY2603618 was well tolerated with no clinically significant adverse events. Study was limited to three patients due to challenges of conducting ADME studies in patients with advanced cancer. Plasma, urine and feces were analyzed for radioactivity, LY2603618 and metabolites. LY2603618 had a half-life of 10.5 h and was the most abundant entity in plasma, accounting for approximately 69% of total plasma radioactivity. The second most abundant metabolites, H2 and H5, accounted for <10% of total circulating radioactivity. The major route of clearance was via CYP450 metabolism. The mean total recovery of radioactivity was 83%, with approximately 72% of the radioactivity recovered in the feces and approximately 11% in the urine. LY2603618 represented approximately 6% and 3% of the administered dose in feces and urine, respectively. A total of 12 metabolites were identified. In vitro phenotyping indicated that CYP3A4 was predominantly responsible for the metabolic clearance of LY2603618. Additionally, aldehyde oxidase was involved in the formation of a unique human and non-human primate metabolite, H5.
Subject(s)
Neoplasms/drug therapy , Phenylurea Compounds/pharmacokinetics , Pyrazines/pharmacokinetics , Administration, Intravenous , Aged , Chromatography, Liquid , Dose-Response Relationship, Drug , Drug Interactions , Feces/chemistry , Female , Half-Life , Humans , Male , Metabolic Clearance Rate , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Middle Aged , Phenylurea Compounds/administration & dosage , Pyrazines/administration & dosage , Tandem Mass SpectrometryABSTRACT
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 (14)C-radiolabeled dose of 1,000 mg of vatalanib administered at steady state, obtained after 14 consecutive daily oral doses of 1,000 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 (14)C radioactivity (38.3 +/- 26.0 microM; mean +/- S.D., n = 7) and vatalanib (15.8 +/- 9.5 microM) 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 (14)C 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]-alpha-(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).
