Preclinical Assessment and Tissue Distribution of Vodobatinib, a Third Generation BCr-Abl 1 Inhibitor

Abstract

Vodobatinib (K0706) is a novel, orally bioavailable Bcr-Abl 1 tyrosine kinase inhibitor designed to overcome resistance mutations such as T3151 in chronic myeloid leukemia. While its clinical efficacy and safety are under investigation, there is limited information on vodobatinib preclinical absorption, distribution, metabolism, and excretion properties and tissue distribution. The objective of this study is to evaluate vodobatinib solubility in phosphate buffer and biorelevant media, metabolic stability in liver microsomes and hepatocytes across species, permeability using MDCK-MDR1 cells, plasma protein binding via equilibrium dialysis, CYP phenotyping and CYP inhibition. Tissue distribution was assessed in male Sprague–Dawley rats following oral administration (2.0 mg/kg), with plasma and tissue samples collected over a 24-hour period. Vodobatinib exhibited poor solubility in phosphate buffer (2.5 µM), but showed improved solubility in biorelevant media. It demonstrated high metabolic stability in liver microsomes and hepatocytes of rats and dogs, with moderate stability in humans. Permeability studies indicated low efflux liability. Plasma protein binding was extensive (>99.8%) across species. Metabolism was primarily mediated by CYP3A4 (≈70%), with minor involvement from CYP2C19 and CYP2D6. CYP inhibition was weak to moderate, suggesting a low potential for drug–drug interactions. Vodobatinib showed high distribution to the liver, intestines, and kidneys, with low brain penetration. Vodobatinib demonstrates a favorable preclinical absorption, distribution, metabolism, and excretion profile, with high metabolic stability, minimal efflux liability, and selective tissue distribution. These findings support its continued clinical development in chronic myeloid leukemia and potentially other Bcr-Abl 1 driven malignancies.