Safety and pharmacokinetics of recombinant human hepatocyte growth factor (rh-HGF) in patients with fulminant hepatitis:
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RESEARCH
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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 Akio Ido1,2*, Akihiro Moriuchi1,2, Masatsugu Numata1,2, Toshinori Murayama3, Satoshi Teramukai4, Hiroyuki Marusawa5, Naohisa Yamaji1,2, Hitoshi Setoyama1,2, Il-Deok Kim1, Tsutomu Chiba5, Shuji Higuchi6, Masayuki Yokode3, Masanori Fukushima4, Akira Shimizu7 and Hirohito Tsubouchi1,2
Abstract Background: Hepatocyte growth factor (HGF) stimulates hepatocyte proliferation, and also acts as an antiapoptotic 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. Methods: Potential 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. Results: We 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. Conclusions: Intravenous 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.
Background Acute liver failure (ALF) is a rare but fatal clinical syndrome marked by the abrupt loss of hepatic cellular function, with the subsequent development of coagulopathy, jaundice and encephalopathy [1-3]. In Japan, ALF with the histological appearance of hepatitis, * Correspondence: [email protected] 1 HGF Hepatic Regeneration Therapy Project, Department of Experimental Therapeutics, Translational Research Center, Kyoto University Hospital, Kyoto, Japan Full list of author information is available at the end of the article
caused by viral infection, autoimmune hepatitis and drug allergy-induced liver injury, is classified as fulminant hepatitis (FH) or as the related disease late-
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