L1 - Journey through the years

Deferiprone (1,2-dimethyl-3-hydroxypyrid-4-one) alias L1, Kelfer, Ferriprox

Professor George J. Kontoghiorghes
Postgraduate Research Institute Science, Technology, Environment and Medicine
Ammochostou 3, CY 3021 Limassol, Cyprus. Tel: ++3575734615, e mail: pri_gjk@cylink.com.cy

Deferiprone is the first oral iron chelator used clinically, mainly in thalassaemia patients, where the annual birth rate worldwide is estimated to be 100000. Deferiprone belongs to the family of the alpha - ketohydroxpyridines, a relatively new class of chelating agents, some of which are naturally occurring. These have high affinity for binding iron and are able to remove it from proteins that are transporting and storing it in the body, largely sparing other biologically important metals. These chelators are stable in conditions that exist in the human digestive system and are readily absorbed.

Deferiprone has undergone extensive trials in hundreds of patients all over the world and has proved to be orally effective in removing excess iron from the body. Studies show that deferiprone is rapidly absorbed from the stomach. It appears in the blood minutes after the capsules are swallowed. In each patient, removal and excretion of iron depends on the dose and frequency of administration of the drug and the amount of iron overload. The major adverse effects, which have been observed in overall about 10% of the patients during worldwide clinical trials over a period of ten years, have been transient musculoskeletal and joint pains, neutropenia and agranulocytosis , gastric intolerance and zinc deficiency. Of these, perhaps the most disturbing is agranulocytosis, affecting less than 0.6% of the patients. In patients with agranulocytosis a substantial reduction or total absence of a group of white cells called granulocytes is observed, which amounts to rendering the body's immune system fatally weak.

This is the reason the focus of the mandatory monitoring procedure is primarily on levels of white blood cells and platelets. The monitoring not only helps to safeguard the well being of the patient but yields valuable data that can contribute to the development of a diagnostic method for agranulocytosis, its prevention and general improvement of the therapy with Deferiprone.

The Journey across the years:

1981.Discovery, design, synthesis and physicochemical characterization.

1981-82. Iron binding, protein and cell studies in-vitro. Animal studies.
1982. Naming of L1 and other alpha - ketohydroxpyridines.
1983. Patented in the UK. Later patented in the USA, EEC and some other countries.
1982-86. Intensive chemical, biochemical, cell and animal studies.
1986. DHSS grants permission for clinical trials in UK.
1987. Simple, cheap synthesis of L1. First ever clinical trials in London.
1988. Multicenter clinical trials begin worldwide.
1989. First publications on joint/musculoskeletal toxicity and agranulocytosis ( London ).
1990. Pharmacokinetic and metabolic properties characterisation of L1 in patients.
1992. Approved BAN and INN name for L1: Deferiprone.
1994. Registration of L1 in India, where now more patients are using L1 than desferal.
1995. Clinical use and multicentre clinical studies continue.
1998. Over 5000 patients in 35 countries have been using L1, some daily for over 10 years.
1999. Registration of L1 in European, South American and Asian countries.
2000. 10th International Conference in Oral Chelators for the treatment of Thalassaemia and other Diseases. 22nd-26th March, 2000. Limassol , Cyprus.

For more information contact Professor George J. Kontoghiorghes at the above address.

Reproduced from : UKTS Website

PS: The above does not mention 1987 : 400 Thals in India put on the largest trial for L1 the in the world.

Kelfer/L1

Kelfer

Deferiprone (1,2-dimethyl-3-hydroxypyrid-4-one) alias L1

The world's first oral iron chelator

What is Kelfer ?
Kelfer (deferiprone) is a iron chelator administered in the form of capsules to patients of thalassaemia major. It is being sold in India since March 1995 commercially.

How does Kelfer act ?
Kelfer acts by combining with the excess iron in the body to form a complex which is excreted in the urine. This over a period of time leads to reduction in the iron overload in the body.

What is the usual dose of Kelfer ?
Studies have found that the optimum dose of Kelfer is 75 mg/kg/day in 2-4 divided doses taken with or without food. In some patients doses upto 100 mg/kg/day may be administered while in others lower doses of 50 mg/kg/day may be sufficient.

What are the side effects of Kelfer ?
In about 20% of patients, joint pains involve knees, hips, elbows or other joints. The pain may be accompanied by swelling in a few cases. This effect is completely reversible on discontinuation of the drug.

In about 12%, Kelfer can reduce white cell counts. This can be dangerous and may predispose the patients to infections. In such situations, the patient may develop fever sore throat etc. The drug should be immediately stopped, the treating physician consulted and appropriate therapy instituted. In some cases, hospitalization may be required till the counts come back to normal.

What are the precautions to be observed while taking Kelfer?
Patients taking Kelfer should be regularly monitored for their blood counts and joint pains. If the total white blood cells falls below 3000/cc of blood or absolute neutrophil counts to below 1500/cc, Kelfer should be immediately discontinued. If the patient develops fever or sore throat, the drug should be discontinued, a blood should be immediately done and if the counts are low (as mentioned above), the physician should be seen immediately.

How is Kelfer available to patients ?
Kelfer is manufactured by Cipla Ltd and is available to patients through Cipla sales offices all over India under certain guidelines. Physicians have to fil up special prescription and patient consent forms prior to initiating therapy with Kelfer. The drug is supplied for a period of 13 months. Subsequently, everytime Kelfer is purchased, a fresh prescription order form has to be filled.

What is the cost of Kelfer therapy ?
For the patients in India the monthly cost of Kelfer therapy works out to Rs.2,000/- on an average with one 250 mg capsule costing Rs.9.75 and one 500 mg capsule costing Rs.16.00

How has Kelfer helped patients of thalassaemia in India ?
The introduction of Kelfer has led to more number of patients taking chelation therapy due to its excellent compliance and low cost. More than 1000 patients have taken Kelfer with good results. Overall, this has led to a better quality of life for thalassaemic patients.

Journey through the years

Study finds Deferiprone (Kelfer/L1/Ferriprox) provides significantly greater cardiac protection