Characterization of preclinical in vitro and in vivo pharmacokinetics properties for KBP-7018, a new tyrosine kinase inhibitor candidate for treatment of idiopathic pulmonary fibrosis.

KBP-7018 is a novel selective tyrosine kinase inhibitor with potential for the treatment of idiopathic pulmonary fibrosis. The objective of this study was to characterize the preclinical pharmacokinetics of KBP-7018 in vitro and in vivo, and then to assess the likelihood of developing KBP-7018 as a clinical candidate. The systemic clearance (CL) of KBP-7018 was relatively low in rodents and monkeys with a value of less than 30% of hepatic blood flow, while it was high in dogs. The steady-state volume of distribution (V ss) ranged from 1.51 L/kg to 4.65 L/kg across the species tested. The maximum concentration (C max) of KBP-7018 occurred at 0.25-6 hours after oral dosing, and the bioavailability was moderate (21%-68%). The human CL (~20% of hepatic blood flow) and V ss (1.6-5.3 L/kg) were predicted by allometric scaling method and together with the other modeling methods indicated low metabolism and acceptable half-time (4.8-19.3 hours) in vivo. Overall, the preclinical data make it amenable to further oral solid dosage from design for the upcoming Phase I trials in human.