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

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.

Discovery of Indolinone-Based Multikinase Inhibitors as Potential Therapeutics for Idiopathic Pulmonary Fibrosis

“…First, KBP-7018 exhibited improved PK profiles compared with nintedanib, as supported by its acceptable oral bioavailability and half-life in all tested species. In a previous study, KBP-7018 showed a significantly lower efflux ratio against P-gp than nintedanib in a Caco-2 cell monolayer transport system, thereby increasing intestinal permeability and absorption in vivo. Second, KBP-7018 demonstrated a highly selectively inhibition of tyrosine kinases compared with nintedanib.…”

Synthesis and Evaluation of Galloyl Conjugates of Flavanones as BMP-2 Upregulators with Promising Bone Anabolic and Fracture Healing Properties

“…The percentage of the analyte remaining intact at different time intervals after incubation was determined by eq , and the graph was plotted between the normal logarithmic of the compound remaining over time. , The curve slope was defined as a depletion rate constant K (min –1 ). The half-life ( t 1/2 ) and in vitro intrinsic clearance (CL ins ) were determined by eqs and , respectively. …”

“…remaining over time. 52,53 The curve slope was defined as a depletion rate constant K (min −1 ). The half-life (t 1/2 ) and in vitro intrinsic clearance (CL ins ) were determined by eqs 2 and 3, respectively.…”

4-(3-Aminoazetidin-1-yl)pyrimidin-2-amines as High-Affinity Non-imidazole Histamine H3 Receptor Agonists with in Vivo Central Nervous System Activity

“…were applied to calculate Cl int in mice, whereas 61 mg of microsomal protein per g liver and 45 g of liver per kg b.w. were applied to calculate Cl int in rats, according to Huang et al 62 and Smith et al 63…”