Ferrate(1-), [[N,N'-1,2-ethanediylbis[N-[[2-(hydroxy-.kappa.O)phenyl]methyl]glycinato-.kappa.N,.kappa.O]](4-)]-, sodium (1:1), (OC-6-13)-

Endpoint summary

Description of key information

The chelating agent HBED is used in patients with iron overload without side effects. HBED is a strong candidate in iron overloaded patients if administered subcutaneously. The majority of iron was excreted in faeces. No adverse effects of chelator administration were noted in patients. 

Additional information

HBED was allowed by FDA (US Food and Drug Administration) to be tested for its safety and efficacy in patients with β-thalassemia who were iron overloaded secondary to transfusion therapy (Grady et al., 1994). In this trial, four patients were admitted to Clinical Research Centre for 24 days, during which time they consumed a low-iron diet and provided 24 -hour specimens of urine and stool. Desferrioxamine (DFO), a known iron chelator with approved activity (here it is reference chelate), was infused subcutaneously at dose level of 60 mg/kg bw over 8 hours on days 5 to 10, with HBED being given orally on days 15 to 20. A stool marker was taken orally before the first and last dose of each drug. Transfusions were given on days 1 and 11 to ensure that the haemoglobin concentration would be the same at the time of administration of each drug. Routine laboratory tests (blood profiles, serum chemistries and urinalyses) were done approximately every 3 days. Special studies (eye examinations, audiograms, and electrocardiograms) were done during days 1 to 4 and prior discharge (days 21 to 24). A pharmacokinetic study was performed upon first administering HBED. Blood samples were collected at 0, 15, 30, 60, 120, 240, and 360 min, which were analysed for HBED and metabolites by HPLC. A complete physical examination was done upon admission and at discharge. The first two patients were given HBED at a dose of 40 mg/kg bw divided i.t.d. This was done as a matter of safety, since this drug had never before been given to humans and there was concern regarding its acidity, especially when taken on an empty stomach. As these patients experienced no difficulties, a permission was received from the FDA to increase the dose to 80 mg/kg bw in subsequent patients.

HBED has been proven to be orally effective, inducing iron excretion in both urine and stool. No significant or consistent changes were noted in blood profiles, serum chemistries, audiograms and in electrocardiograms of the patients. They experienced no adverse side effects and were enthusiastic about the study and have encouraged others to participate. DFO caused the excretion of significantly more iron than excreted considering the serum ferritin levels of patients and their history of compliance with chelation therapy. DFO-induced faecal excretion of iron accounted for more than half of that excreted in three of the four patients. HBED caused an increase in both urinary and faecal iron excretion , with faecal excretion accounting for more than 50% of the total in three of patients. Upon increasing the dose of HBED from 40 to 80 mg/kg bw, total iron excretion increased from 11.4% of that due to DFO to 16.6%. Zinc excretion may be slightly enhanced in response to HBED, but not to levels considered to be toxic.

In a patent the use of a mono-cationic salt of N,N'-bis(2 -hydroxybenzyl)ethylenediamine-N,N'-diacetic acid (HBED) in iron chelating therapy is disclosed (Bergeron, 2003). In particular, the invention relates to the subcutaneous use of a mono cationic salt of HBED for treating a human with a disease treatable by an iron chelator such as iron overload, especially tranfusional iron overload. As there exist no specific mechanism in the human (or simian) body, which eliminates excess of iron, this would lead to saturated protein complexes (ferritin and hemosiderin), when the body is overloaded with iron. This results in excess iron being deposited in tissues which induces iron toxicity and ultimately leads to peroxidative tissue damage. The principle of iron chelators is that they transform the deposited iron back into a soluble form that is then capable of excretion.

The method of administration that has been found to be surprisingly effective is the subcutaneous administration of mono-cationic salt of HBED. Generally, about 5 micromoles (µmoles) to about 500 micromoles of the active moiety i.e. HBED, will be administered to a patient on a per kilogram (kg) basis. Suitable doses are in the general range from about 1 to about 200 mg/Kg bw of the recipient per day, preferably in the range from about 10 to 80 mg/kg bw as the active moiety (HBED).