Absorption, Distribution, Metabolism, and Excretion of 14 C-Labeled Tivantinib (ARQ 197) in Healthy Male Subjects

Tivantinib (ARQ 197), a selective, oral, non-ATP-competitive, small-molecule inhibitor of c-MET receptor tyrosine kinase, is being evaluated in combination with other agents in non-small cell lung cancer, colorectal cancer, and hepatocellular carcinoma (HCC), and as a single agent in HCC. This study assessed the absorption, distribution, metabolism, and excretion of tivantinib in healthy subjects. Methods: A phase 1, open-label study was conducted in healthy, male, nonsmoking subjects (age, 18 to 45 years; body mass index, 19 to 29 kg/m 2 ). A single 360-mg oral dose of 14 C-tivantinib (~250 µCi) was administered ~5 min after consumption of a standard high-fat meal (breakfast). Blood, feces, and urine samples were collected for tivantinib and radioactivity analysis for a maximum of 16 days postdose. Study endpoints included pharmacokinetic parameters associated with total radioactivity in blood and plasma and tivantinib in plasma, mass balance (rate and extent of excretion) of total 14 C radioactivity in urine and feces, and adverse events (AEs). Plasma, urine, and fecal samples were also analyzed for metabolite identification. Results: Six subjects (all CYP2C19 extensive metabolizers) participated in this study. Median time to maximal concentration (t max ) for tivantinib in plasma and total radioactivity in plasma and whole blood were 4, 6, and 6 hours, respectively. Mean terminal half-life (t 1/2 ) for tivantinib in plasma and total radioactivity in plasma and whole blood were 11.7, 20.7, and 13.6 hours, respectively. Based on area under the curve (AUC), tivantinib constituted ~12% of total radioactivity in plasma, indicating the existence of substantial amounts of circulating tivantinib metabolite(s). Eight tivantinib metabolites were identified in plasma, and 4 were considered major metabolites based on their relative plasma exposure. The mean whole blood to plasma AUC inf ratio (AUC b :AUC p ) was 0.609, indicating that most of the total radioactivity resided in plasma and was not highly associated with red blood cells. Mean ± SD recovery of radioactivity in feces and urine was 87.2% (feces = 68.2% ± 3.80%; urine = 19.0% ± 2.42%). Parent tivantinib was not detected in urine and trace amounts were detected in feces. Urinary and fecal metabolites were oxidative and subsequently conjugated molecules. Three subjects (50%) developed 12 treatment- emergent AEs; all were mild in severity and none resulted in treatment discontinuation. Conclusions: Tivantinib was rapidly absorbed and metabolized after oral administration, and 87% of total radioactivity was recovered in urine and feces. Parent tivantinib was not detected in urine and only trace amounts were detected in feces. The fact that all the urinary and fecal metabolites are oxidative and subsequently conjugated molecules suggests near complete absorption of tivantinib when administered under fed conditions.