title: 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.
abstract: BACKGROUND
  Hepatocyte 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.
  
  
  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.
authors.affiliation: HGF Hepatic Regeneration Therapy Project, Department of Experimental Therapeutics, Translational Research Center, Kyoto University Hospital, Kyoto, Japan. ido-akio@m2.kufm.kagoshima-u.ac.jp
authors.forename: Akio
authors.initials: A
authors.lastname: Ido
authors.forename: Akihiro
authors.initials: A
authors.lastname: Moriuchi
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Numata
authors.forename: Toshinori
authors.initials: T
authors.lastname: Murayama
authors.forename: Satoshi
authors.initials: S
authors.lastname: Teramukai
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Marusawa
authors.forename: Naohisa
authors.initials: N
authors.lastname: Yamaji
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Setoyama
authors.forename: Il-Deok
authors.initials: ID
authors.lastname: Kim
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Chiba
authors.forename: Shuji
authors.initials: S
authors.lastname: Higuchi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yokode
authors.forename: Masanori
authors.initials: M
authors.lastname: Fukushima
authors.forename: Akira
authors.initials: A
authors.lastname: Shimizu
authors.forename: Hirohito
authors.initials: H
authors.lastname: Tsubouchi
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001794:Blood Pressure; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D006501:Hepatic Encephalopathy / Q000188:drug therapy; D006505:Hepatitis / Q000188:drug therapy* / Q000503:physiopathology; D017228:Hepatocyte Growth Factor / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D006801:Humans; D007275:Injections, Intravenous; D007668:Kidney / Q000473:pathology; D008297:Male; D008875:Middle Aged; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D016019:Survival Analysis; D013552:Swine; D013556:Swine, Miniature
chemical_list: C066855:HGF protein, human; D011994:Recombinant Proteins; D017228:Hepatocyte Growth Factor