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

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.

Pharmacokinetic Modeling of Hepatocyte Growth Factor in Experimental Animals and Humans

“…12 Recent phase I/II clinical studies in patients with some of those organ failures revealed no severe side effects of HGF treatment in humans. 13,14 However, the multiple biological activities of HGF do raise the possibility that undesirable effects might occur after systemic administration without careful control of the dose regimen. Therefore, it is essential to understand the overall pharmacokinetics of HGF in humans.…”

Pharmacokinetics and Pharmacodynamics following Intravenous Administration of Recombinant Human Hepatocyte Growth Factor in Rats with Renal Injury

“…In recent years, phase I clinical studies by intravenous administration of recombinant HGF have begun, and a critical toxic effect has not been noted in these studies [10]. We have previously indicated that the basic pharmacokinetic profiles and parameters obtained from experimental animal species (mouse, rat and monkey) could be extrapolated to those in humans [29].…”

“…Thus, the potential tissues for clinical development of HGF include the kidney and liver. Phase I clinical trials of recombinant human HGF have been conducted in patients with fulminant hepatitis [10]. …”

A Therapy for Liver Failure Found in the JNK Yard

“…Transient MKK4 inhibition therefore has potential in the therapy of acute liver failure. This would require fast-acting MKK4 blockage to facilitate restoration of a critical hepatocyte mass before aggravation of the illness to multi-organ failure (Ido et al, 2011). For this, antisense oligonucleotides could be used that reach hepatocytes and knock down targeted genes within hours after intravenous injection (Ng et al, 2012).…”