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.
School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, People's Republic of China.
Zhenhua
Z
Huang
School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, People's Republic of China.
Heran
H
Li
KBP BioSciences Co. Ltd., Jinan, Shandong, People's Republic of China.
Qian
Q
Zhang
KBP BioSciences Co. Ltd., Jinan, Shandong, People's Republic of China.
Xiaojuan
X
Tan
School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, People's Republic of China.
Fangzheng
F
Lu
School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, People's Republic of China.
Hongzhuo
H
Liu
School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, People's Republic of China.
Sanming
S
Li
D061605:Administration, Intravenous; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001711:Biotransformation; D018938:Caco-2 Cells; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics; D004285:Dogs; D004347:Drug Interactions; D004355:Drug Stability; D006207:Half-Life; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000188:drug therapy* / Q000201:enzymology; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D007408:Intestinal Absorption; D008252:Macaca fascicularis; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology; D008954:Models, Biological; D058990:Molecular Targeted Therapy; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018570:Risk Assessment; D015398:Signal Transduction / Q000187:drug effects; D013045:Species Specificity
D065692:Cytochrome P-450 CYP3A Inhibitors; D007211:Indoles; C000606308:KBP-7018; D047428:Protein Kinase Inhibitors; D020794:Receptor Protein-Tyrosine Kinases
KBP-7018; idiopathic pulmonary fibrosis; pharmacokinetics; tyrosine kinase inhibitor