(T1030-10-67) Pharmacokinetic Characterization of ETN101, a Novel Anti-cancer Agent and Its Metabolites in Rats and Dogs

Purpose: ETN101 is a novel multiple tyrosine-kinase inhibitor reported to have potent therapeutic effects against hepatocellular carcinomas. The aim of this study was to characterize the pharmacokinetics of ETN101 and its metabolites in rats and dogs.

Methods: This study was performed to characterize the pharmacokinetic disposition of ETN101 and its metabolites following i.v. and oral administrations of ETN101 in rats and dogs. Following i.v. and oral administrations of ETN101 at doses of 10, 20, and 40 mg/kg, blood samples were collected at predetermined time points and pharmacokinetic parameters of ETN101, M1, and M2 were calculated in SD rats. In 20 mg/kg i.v. injected group, urine and feces were collected to characterize the excretion rate. The tissue distribution of ETN101 and its metabolites were investigated after multiple oral administrations of ETN101 at a dose of 20 mg/kg for 5 consecutive days. The ETN101 was also intravenously and orally administered to Beagle dogs and pharmacokinetic parameters were estimated.

Results: In rats, ETN101 and its metabolites showed multi-exponential decline following i.v. injection of ETN101 and the calculated half-lives were 10.3 ± 1.98 h for ETN101, 41 ± 11.99 h for M1, and 23.73 ± 4.07 h for M2. Following oral administration, ETN101 was slowly absorbed (T_max=3.42-5.33 h), and the average absolute bioavailability was calculated to be 62.24 ± 8.1%. As a result of the excretion study, about 1, 1.5, and 3% of intravenously dosed ETN101 were excreted via feces as ETN101, M1, and M2, respectively. The urinary excretion of ETN101, M1, and M2 was observed minimal in rats, with less than 0.1% of a fraction of the dose. After multiple oral administrations, ETN101 was mainly distributed into the lung, kidney, and liver. The metabolites were distributed into the liver and kidney. In Beagle dogs, the half-lives of ETN101 and M1 were calculated as 3.2 ± 1.83 and 3.3 ± 0.72 h, respectively. Upon oral administration of ETN101, ETN101 was slowly absorbed (T_max=5 h) and the average absolute bioavailability was estimated to be 74.57 ± 6.16%.

Conclusion: In the present study, the pharmacokinetics of ETN101 and its metabolites in rats and dogs after i.v. injection and oral administration was investigated. Overall, ETN101 was slowly absorbed following oral administration and showed relatively high absolute bioavailability. In rats, ETN101 and its metabolites were mainly distributed to liver, kidney, and lung. About 5% of absorbed amount of ETN101 was excreted via feces, and urinary excretion was minimal. This is the first report about in vivo pharmacokinetics of ETN101, a new oral anti-cancer agent against hepatocellular carcinoma. The drug showed high absolute bioavailability and significant amount was distributed to liver. These results are expected to be used for further drug development and designing clinical trials.

Acknowledgements: This research was supported by Korea Drug Development Fund funded by Ministry of Science and ICT, Ministry of Trade, Industry, and Energy, and Ministry of Health and Welfare (RS-2022-00165725, Republic of Korea).