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    已发表论文

    治疗特发性肺纤维化的酪氨酸激酶抑制剂候选药物 KBP-7018 的临床前体内和体外的药代动力学特征研究

     

    Authors Huang Z, Li H, Zhang Q, Tan X, Lu F, Liu H, Li S
    Received 17 February 2015
    Accepted for publication 18 March 2015
    Published 5 August 2015 Volume 2015:9 Pages 4319—4328
    DOI http://dx.doi.org/10.2147/DDDT.S83055
    Checked for plagiarism Yes
    Review by Single-blind
    Peer reviewer comments 3
    Editor who approved publication:  Professor Shu-Feng Zhou


    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 (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.
    Keywords: idiopathic pulmonary fibrosis, tyrosine kinase inhibitor, pharmacokinetics, KBP-7018







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