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

Abstract

Zhenhua Huang,1 Heran Li,1 Qian Zhang,2 Xiaojuan Tan,2 Fangzheng Lu,1 Hongzhuo Liu,1 Sanming Li11School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 2KBP BioSciences Co. Ltd., Jinan, Shandong, People’s Republic of ChinaAbstract: 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 (Vss) ranged from 1.51 L/kg to 4.65 L/kg across the species tested. The maximum concentration (Cmax) 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 Vss (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.Keywords: idiopathic pulmonary fibrosis, tyrosine kinase inhibitor, pharmacokinetics, KBP-7018