Received for publication February 23, 2006.
Revised June 2, 2006.
Accepted for publication July 25, 2006.

METABOLISM AND DISPOSITION OF VATALANIB (PTK787/ZK 222584) IN CANCER PATIENTS

Abstract

Vatalanib (PTK/ZK) is a new oral antiangiogenic molecule that inhibits all known vascular endothelial growth factor (VEGF) 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. Eight patients were given a single oral ¹⁴C-radiolabeled dose of 1000 mg vatalanib administered at steady state obtained following 14 consecutive daily oral doses of 1000 mg non-radiolabeled vatalanib. Plasma, urine, and feces were analyzed for radioactivity, vatalanib, and its metabolites. Metabolite patterns were determined by radio-HPLC with off-line microplate solid scintillation counting and characterized by LC-MS. Vatalanib was well tolerated. The majority of AEs corresponded to common toxicity criteria grade 1 or 2. Two patients had stable disease for at least 7 months. Plasma C_max of ¹⁴C radioactivity (38.3 ± 26.0 µmol/L; mean ± S.D., n = 7) and vatalanib (15.8 ± 9.5 µmol/L) 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 and NVP AAW378/ZK 261557, 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).

Key words: anticancer agents, drug absorption, drug disposition, excretion, half-life, HPLC, mass spectrometry, metabolite identification, oral absorption, pharmacokinetics

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