Safety and pharmacokinetics of recombinant human hepatocyte growth factor (rh-HGF) in patients with fulminant hepatitis: a phase I/II clinical trial, following preclinical studies to ensure safety

Journal of Translational Medicine

Research

Masayuki Yokode¹  Toshinori Murayama¹  Masanori Fukushima²  Satoshi Teramukai²  Akira Shimizu³  Tsutomu Chiba⁴  Hiroyuki Marusawa⁴  Il-Deok Kim⁵  Hirohito Tsubouchi⁶  Akihiro Moriuchi⁶  Naohisa Yamaji⁶  Masatsugu Numata⁶  Hitoshi Setoyama⁶  Akio Ido⁶  Shuji Higuchi⁷ 

[1] Department of Clinical Innovative Medicine, Translational Research Center, Kyoto University Hospital, Kyoto, Japan;Department of Clinical Trial Design and Management, Translational Research Center, Kyoto University Hospital, Kyoto, Japan;Department of Experimental Therapeutics, Translational Research Center, Kyoto University Hospital, Kyoto, Japan;Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan;HGF Hepatic Regeneration Therapy Project, Department of Experimental Therapeutics, Translational Research Center,Kyoto University Hospital, Kyoto, Japan;HGF Hepatic Regeneration Therapy Project, Department of Experimental Therapeutics, Translational Research Center,Kyoto University Hospital, Kyoto, Japan;Digestive Disease and Life-style Related Disease, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan;R&D and Corporate Integration, Kyoto University Graduate School of Medicine, Kyoto, Japan;

关键词: Hepatocyte Growth Factor;    Hepatic Encephalopathy;    Liver Regeneration;    Fulminant Hepatitis;    Hepatic Progenitor Cell;   

DOI  :  10.1186/1479-5876-9-55

 received in 2011-02-01, accepted in 2011-05-08,  发布年份 2011

来源: Springer

【 摘 要 】

BackgroundHepatocyte growth factor (HGF) stimulates hepatocyte proliferation, and also acts as an anti-apoptotic factor. Therefore, HGF is a potential therapeutic agent for treatment of fatal liver diseases. We performed a translational medicine protocol with recombinant human HGF (rh-HGF), including a phase I/II study of patients with fulminant hepatitis (FH) or late-onset hepatic failure (LOHF), in order to examine the safety, pharmacokinetics, and clinical efficacy of this molecule.MethodsPotential adverse effects identified through preclinical safety tests with rh-HGF include a decrease in blood pressure (BP) and an increase in urinary excretion of albumin. Therefore, we further investigated the effect of rh-HGF on circulatory status and renal toxicity in preclinical animal studies. In a clinical trial, 20 patients with FH or LOHF were evaluated for participation in this clinical trial, and four patients were enrolled. Subjects received rh-HGF (0.6 mg/m2/day) intravenously for 12 to 14 days.ResultsWe established an infusion method to avoid rapid BP reduction in miniature swine, and confirmed reversibility of renal toxicity in rats. Although administration of rh-HGF moderately decreased BP in the participating subjects, this BP reduction did not require cessation of rh-HGF or any vasopressor therapy; BP returned to resting levels after the completion of rh-HGF infusion. Repeated doses of rh-HGF did not induce renal toxicity, and severe adverse events were not observed. Two patients survived, however, there was no evidence that rh-HGF was effective for the treatment of FH or LOHF.ConclusionsIntravenous rh-HGF at a dose of 0.6 mg/m2 was well tolerated in patients with FH or LOHF; therefore, it is desirable to conduct further investigations to determine the efficacy of rh-HGF at an increased dose.

【 授权许可】

CC BY   
© Ido et al; licensee BioMed Central Ltd. 2011