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

Area of Science:

• Pharmacology
• Drug Metabolism
• Oncology

Background:

• Vodobatinib (K0706) is a novel tyrosine kinase inhibitor targeting Bcr-Abl1, including resistance mutations like T315I in chronic myeloid leukemia (CML).
• Limited preclinical data exists on vodobatinib's absorption, distribution, metabolism, and excretion (ADME) properties and tissue distribution.

Purpose of the Study:

• To comprehensively evaluate the preclinical ADME profile of vodobatinib.
• To assess solubility, metabolic stability, permeability, plasma protein binding, CYP interactions, and tissue distribution of vodobatinib.

Main Methods:

• Solubility assessed in phosphate buffer and biorelevant media.
• Metabolic stability evaluated in liver microsomes and hepatocytes (rat, dog, human).
• Permeability (MDCK-MDR1), plasma protein binding (equilibrium dialysis), CYP phenotyping/inhibition, and rat tissue distribution were determined.

Main Results:

• Vodobatinib exhibited poor aqueous solubility but improved solubility in biorelevant media.
• High metabolic stability in rat and dog liver preparations, moderate in human; low efflux liability observed.
• Extensive plasma protein binding (>99.8%), primary metabolism via CYP3A4, weak-to-moderate CYP inhibition.
• High distribution to liver, intestines, kidneys; low brain penetration in rats.

Conclusions:

• Vodobatinib possesses a favorable preclinical ADME profile, characterized by high metabolic stability and selective tissue distribution.
• Minimal drug-drug interaction potential due to weak-to-moderate CYP inhibition.
• These findings support the continued clinical development of vodobatinib for CML and other Bcr-Abl1-driven malignancies.