Deferiprone (Ferriprox) as newer iron Chelator in Thalassaemia major patients

 

Jinal L. Chaudhary*, Sanjesh G Rathi, Sanket Shah, Jigna T Patel, Sohansinh Vaghela

Department of Pharmacy Practice Saraswati Institute of Pharmaceutical Sciences, Dhanap, Ghandhinagar.

 

ABSTRACT:

The present study was on Deferiprone is the first line therapy in treatment of thalassemia patients either alone or in combination with other available chelating agents. Advantage over other iron chelators is, oral mode of administration, better compliance, being more affordable, similar efficacy in reducing iron burden in patients with severe haemosiderosis. Long-term Deferiprone therapy is generally well tolerated, and a longer duration of therapy is warranted in patients with severe iron overload. Deferiprone offers an acceptable second line alternative. Patients with thalassemia major for whom deferoxamine therapy is contra-indicated or who present serious toxicity with deferoxamine therapy. A comparison between the pre-clinical data and the safety data is very difficult in this case. The most important adverse reactions are agranulocytosis and neutropenia whose incidence is 1.2% and 6% respectively. The amount of long-term data is limited, but in view of the indication this was accepted. As a weekly monitoring of blood counts is accepted for the safety of the product.

 

 

 

INTRODUCTION:

Thalassemia major (TM) is a rare hereditary disease characterized by severe anemia, requiring a life-long program of periodic blood transfusions to sustain growth, normal physiological development and extend survival. Patients may need blood transfusions for various reasons: to improve oxygen carrying in cases of aplastic anemia or severe hemolysis, replace blood volume in cases of splenic sequestration, provide protection against imminent acute chest syndrome or septicemia, and improve the rheological properties of blood to prevent initial or recurrent cerebral thrombosis, prevent recurrent priapism, and reduce perioperative complications. Transfusion iron and iron accumulation through increased gastrointestinal absorption as a consequence of increased erythropoiesis often results in severe iron overload in sickle cell patients⁴. Frequent blood transfusions result in iron overload, which may also be aggravated by inappropriate increases in iron absorption from the gastrointestinal tract.

 

Nearly thirty million people are carriers of beta thalassemia alone in India and 8-10 thousand babies with thalassemia major are born every year in India. All these children with thalassemia major are potential candidates to develop iron overload and toxicity from blood transfusions.

 

Table: 1 Information Prevalence of various types of thalassemia in Asian countries

Country	Average carrier rate (%) for common thalassemia and Hb disorders
	α0-thalassemia	α+-thalassemia*	β-thalassemia	Hb E
India	<1	10–13	3–4	4–30
Sri Lanka	<1	13.6	1–5	0.5
Maldives	<1	28	18	0.8
Myanmar	NA	10	1–5.3	4–48
Thailand	2.2–9	8–30	1–3	10-50
Cambodia	1	15.5	2.8	10-54
Laos	NA	11	5	>30
Vietnam	NA	3.5	4	10-20
Southern China	15	1-5	1.7	NA
Hong Kong	2.2	2.3	3.5	1-2
Taiwan	5	2.3	1.1	<1
Singapore	2-3	1-3	0.93	0.64
Malaysia	4.5	16	4.5	1-3
Indonesia	<1	3-20	3	1-33
Philippines	5	2.2	1	NA

NA not available, *α⁺ thalassemia included: Deletional (-α) and Non-Deletional (α^Tα or αα^T) types

 

MATERIAL AND METHODS:

Ferriprox (Deferiprone):

Deferiprone was First use human in 1987 (UK), First approved in European Union (EU) in 1999 (Currently in 61 countries), Approved indication in EU is “For the treatment of iron overload in patients with thalassemia major when deferoxamine therapy is contraindicated or inadequate.²

 

Table: 2 Deferiprone Regulatory Timeline

Sr. No	Recorded years date and days	Submission Indication
1	July 15, 1994	Original IND
2	December 12, 2001	Orphan designation
3	January 26, 2004	Fast Track approved
4	January 29, 2009	NDA submitted
5	November 30, 2009	Complete Response (CR) letter

 

Ferriprox contains Deferiprone, a bidendate chelating agent that chelates trivalent iron cations (Fe3+) in a3:1 (deferiprone:iron) ratio. It is indicated for the treatment of iron overload in patients with TM for whom deferoxamine therapy is contraindicated.

 

Ferriprox is given orally as 25-mg/kg body weights, three times a day for a total daily dose of 75-mg/kgbody weights.

 

Chemical, pharmaceutical and biological aspects of deferiprone

Deferiprone

 

Description:

Deferiprone is an orally active synthetic iron chelator. Chemically, deferiprone is designated as 3-hydroxy-1,2-dimethyl-4(1H)-pyridone. Deferiprone is a white to off-white crystalline powder with a molecular formula of C7H9NO2 and a molecular weight of 139.15. It has a melting range of 272°C to 278°C. The CAS Registry Number for Deferiprone is 30652-11-0 each bottle contains 100 tablets. FERRIPROX oral solution is a clear, reddish-orange coloured liquid with a peppermint and cherry-flavored aroma. Each mL of oral solution contains 100 mg Deferiprone as active substance and the following excipients: purified water, hydroxyethyl cellulose, glycerol, hydrochloric acid, artificial cherry flavours, and peppermint oil, sunset yellow FCF and sucralose.⁷

 

Pharmacological aspects:

Pharmacodynamic Properties:

Deferiprone is a bidentate ligand which binds to iron in a 3:1 molar ratio and therefore removes excess of iron from the body. The precise mechanism by which deferiprone is effective in promoting iron excretion and preventing the progression of iron accumulation is unknown.

 

Pharmacokinetic Properties:

Deferiprone is rapidly absorbed from the upper part of the gastro-intestinal tract.Peak serum concentration is reported to occur 45 to 60 minutes following a single dose in fasted patients. Deferiprone is cleared from plasma by metabolism, predominantly to a glucuronide metabolite. The rate of clearance has not been determined. In humans, Deferiprone is eliminated mainly via the kidneys with reports of 75% to 90% of the ingested dose being recovered in the urine in the first 24 hours, mainly in the form of the glucuronide metabolite and the iron-Deferiprone complex. Only 5% of an administered dose of deferiprone is excreted unchanged in the urine. The elimination half-life in most patients is 2 to 3 hours.⁶

 

Ferriprox is indicated for the treatment of iron overload in patients with Thalassaemia major who are unable to take desferrioxamine therapy or in whom desferrioxamine therapy has proven ineffective. Ferriprox is contraindicated in patients who have demonstrated hypersensitivity to the active substance or any of the excipients, have a history of recurrent episodes of neutropenia, have a history of agranulocytosis, are pregnant or breast-feeding. A monitoring of plasma Zn2+, as well as supplementation in case of a deficiency is recommended. Patients should be informed that a reddish/brown discoloration of the urine is commonly associated with deferiprone use which is reported to be due to the excretion of the iron-deferiprone complex, which is a chromophore. The genotoxic potential of deferiprone was evaluated in a set of in vitro and in vivo tests (non iron-loaded models). Deferiprone was non-mutagenic in the bacterial reverse mutation assay, however, it did display genotoxic characteristics in non-iron loaded in vitro and in vivo systems. No data on the carcinogenic properties are available. Ferriprox film-coated tablets: Store below 25°C.Ferriprox oral solution: Store below 30°C, protect from light. After first opening, store at 2°C to 8°C (Refrigerate. Do not freeze.), and use within 35 days

 

Dosage and Administration:

FERRIPROX is given as 25mg/kg body weight, orally, three times a day for a total daily dose of 75mg/kg body weight. Dosage per kilogram body weight should be calculated to the nearest half tablet or to the nearest 2.5 mL. See Dosage Table below to obtain a dose of about 75mg/kg/day, use the dose suggested in the following table for the body weight of the patient.

 

Table: 3 Dosage Table

Body Weight (kg)	Total Daily Dose (mg)	Dose (mg, three times/day)	500 mg film-coated tablets	100 mg/ML oral solution
			Number of tablets (three times/day)	ML (three times/day)
20	1500	500	1.0	5.0
30	2250	750	1.5	7.5
40	3000	1000	2.0	10.0
50	3750	1250	2.5	12.5
60	4500	1500	3.0	15.0
70	5250	1750	3.5	17.5
80	6000	2000	4.0	20.0
90	6750	2250	4.5	22.5

 

FERRIPROX tablets are available in HDPE containers of 100 tablets with child resistant closures. FERRIPROX oral solution is available in 250mL and 500mL round amber polyethylene terephthalate (PET) bottles with white polypropylene child resistant pictorial caps. Each pack contains one bottle and one graduated plastic dosing cup.⁷

 

METHOD:

Clinical Study of Ferriprox:

There were many study conducted for Deferiprone alone and combination with Desferrioxamine to measure the effect of both drugs. One of them was compare Desferrioxamine (DFX) alone with a prospective combined therapy with Desferrioxamine (DFX) and Deferiprone (L1) in betathalassemia major patients with iron overload. they studied 91 patients with beta thalassemia major attending the daycare unit for regular transfusional support. They received packed red cells every 3–4 weeks to maintain pretransfusion hemoglobin concentration above 9g/dl. They had been receiving DFX at a daily dose of 40mg kg−1day−1 by subcutaneous infusion for 8–10 h on 4–5 nights each week for the past several years. However, due to various reasons, they had developed considerable transfusion iron overload. These patients were allocated to prospectively receive additional therapy with oral iron chelator L1 at 75mg kg−1 day−1 body weight in three divided doses with food after informed consent and continued to receive treatment with DFX as per the above dosage. Results also demonstrate a significant statistical improvement after as little as 6 months of combination therapy. Furthermore, these improvements lead to a progressive fall in the mean serum ferritin. The availability of deferiprone (L1), an oral iron chelator, has been a significant advance in the therapeutic armamentarium but when used alone it is not as potent as DFX and can cause significant toxicity if higher doses are used. At a dose of 75mg/kg/day body weight it appears to be safe and effective. Furthermore, when combined with DFX there is a significant improvement in efficacy of iron chelation.⁴ Since 1987 deferiprone was evaluated in 17 countries at 32 centres before being released in India.

 

All these studies have revealed that iron excretion on L1 depends upon its dose, frequency of administration, levels of free iron, and levels of iron overload in addition to the erythropoietic activity. Deferiprone in standard doses exerts a negative iron balance resulting in lowering of serum ferretin levels to nearly 50 percent of initial levels over 12-18 months^[4]. Overall, urinary iron excretion on the equivalent dose of L1 and desferrioxamine (DFO) were almost identical. In addition to urinary iron excretion 20-30% of iron is also excreted through faeces in patients on DFO.

 

However, it can be used in higher doses in the presence of very high serum ferritin levels. Effect of Deferiprone on hepatic iron concentration is of greater concern because of hepato-toxicity as a result of iron overload in multitransfused thalassemia children. There have been four prospective studies to evaluate the effect of Deferiprone on hepatic iron concentration^[5]. First study observed a decrease in hepatic iron concentration following oral deferiprone therapy, U while the second study revealed an increase in hepatic iron concentration over prolonged therapy. Hoff brand and colleagues observed that a higher proportion of patients treated with oral Deferiprone had hepatic iron concentration above 268 umol gm of dry liverlL Recently, Oliveri et a114 showed that long term Deferiprone therapy was not able to maintain hepatic iron concentration below hepatotoxic levels. In 39% (7 of 18) of patients hepatic iron was in dangerous concentration and progression of hepatic fibrosis was seen in 5 of14 (35.7%) patients. Based upon these observations authors suggested that long term deferiprone therapy may be hepatotoxic and can result in the progression of hepatic fibrosis. Both these adverse factors are associated with worsening of fibrosis. Results of these four studies are discordant and therefore a large multicentric well controlled study is essential to resolve the issue of hepatic iron concentration and hepatic fibrosis

 

Table: 4 Effect of Deferiprone on Serum Ferritin (AIIMS Study)

Dose of L1)	Mean serum Ferritin (ng/ml)
	N	Initial	Period(months)
			4	6	12
A 50/mg/kg/d	30	6232.0	5163.6	5076.3	4007.9
B 75/mg/kg/d	21	7214.4	5349.5	4788.1	3785.2
C Control	24	3680.6	4790.0	4572.2	7750.5

Group A Initial vs. 12 months P < 0.01 fall; Group B Initial vs. 12 months p < 0.01 fall; Group C Initial vs. 12 months p < 0.01 rise

 

One article shows long term effect of Deferiprone especially in Asian Indians. The present study is possibly the largest study on deferiprone use in patients with thalassemia major reported from a single tertiary care cente.³ It showed the efficacy as assessed by repeated serum ferritin measurements at mean dose of 70.2 mg/kg/day of deferiprone, and individual dose requirement may vary. Overall, a dose range of 44–100 mg/kg/day of deferiprone was effective in controlling the body iron load, as determined by serum ferritin levels.

 

Therefore, the dose needs individualized with proper monitoring. Deferiprone (L1) has revolutionized the treatment of thalassemia. Its advantages over “gold standard” DFO include: oral mode of administration, better compliance, being more affordable (about one tenth the cost of DFO), similar efficacy in reducing iron burden in patients with severe haemosiderosis.²

 

Table: 5 Characteristics of available iron chelating agents

Parameters	Deferoxamine	Deferiprone
Route of administration	Intravenous infusion	Oral
Plasma half	20–30 min	3-4h
Route of iron excretion	Urinary and some fecal	Primarily urinary
Tissue and cell penetration	High to hepatocytes, moderate to reticuloendothelial system and myocytes	Low to hepatocytes, good to red cells and myocytes
Cardiac protective effect	Can reverse cardiac failure when given as a continuous infusion	Greater than deferoxamine
Adverse effects	Auditory and retinal toxicity; effects on bone growth and cartilage	Arthropathy, neutropenia, agranulocytosis, abdominal discomfort

 

Heart failure patient:

Seventy percent of the deaths in patients with b-thalassemia major are due to cardiac decompensation as a result of iron overload from long-term transfusions in patients with poor iron chelation, heart failure followed by death is usually unavoidable^[2]. Only one patient with b thalassemia major and severe cardiac failure due to iron overload who was successfully treated with high-dose ambulatory intravenous DFX has been reported. On the other hand, cardiac MRI, a noninvasive method, is now able to assess the severity and early diagnosis of cardiac iron loading, to produce clearer, accurate, and reproducible pictures as well as to monitor the effectiveness of different chelation regimens. In this report, we have shown the effectiveness of the combined therapy with L1 and DFX in regressing severe heart failure by clinical examination, in improving cardiac function by Echocardiographic studies^.

 

Since the release of the drug in India, nearly 2000 thalassemic children have received deferiprone therapy. Toxicity of the drug has been less in control studies, possibly as most children received the drug in lesser dose

 

RESULT:

Amongst other available chelating agents for iron over-load, Deferiprone is the first line therapy in treatment of thalassemia patients either alone or in combination with other available chelating agents. Advantage over other iron chelators is, oral mode of administration, better compliance, being more affordable, similar efficacy in reducing iron burden in patients with severe haemosiderosis. Long-term Deferiprone therapy is generally well tolerated, and a longer duration of therapy is warranted in patients with severe iron overload. Deferiprone offers an acceptable second line alternative. Patients with thalassemia major for whom deferoxamine therapy is contra-indicated or who present serious toxicity with deferoxamine therapy. A comparison between the pre-clinical data and the safety data is very difficult in this case. The most important adverse reactions are agranulocytosis and neutropenia whose incidence is 1.2% and 6% respectively. The amount of long-term data is limited, but in view of the indication this was accepted. As a weekly monitoring of blood counts is accepted for the safety of the product.

 

REFERENCES:

1.     Singer T, MD, Hematologist, Children’s Hospital & Research Center Oakland Perspectives, Newsletter of the Northern California Thalassemia Center - fall 2005 p-4

2.     Suh KR, MD, PhD, “Ferriprox (Deferiprone) NDA 21-825 FDA Presentation to Oncologic Drugs Advisory Committee. 2011; 1-37.

3.     Ferriprox, “The Initial Scientific Discussion and Scientific Discussion on Procedures, which have been Finalized Before 1 June 2004” @ EMEA 2005, 1.

4.     Anderson LJ, Holden S, Davis B, Prescott E, Charrier CC, Bunce NH, Firmin DN, Wonke B, Porter J, Walker JM, Pennell Cardiovascular T2-star (T2*) magnetic resonance for the early diagnosis of myocardial iron overload. Eur Heart J, 2001; 22: 2171–79.

5.     Westwood M, Anderson L, Firmin DN, Gatehouse PD, Charrier CC, Wonke B, Pennell DJ A single breath-hold multiecho T2* cardiovascular magnetic resonance technique for diagnosis of myocardial iron overload. J Magn Reson Imaging, 2003; 18:33–39.

6.     Ehlers KH, Giardina PJ, Lesser ML, Engle MA, and Hilgartner MW Prolonged survival in patients with beta-thalassemia major treated with deferioxamine. J Pediatr ,1991;540–545

7.     Mourad FH, Hoffbrand AV, Sheikh-Taha M, Kousa S. Comparison between desferrioxamine and combined therapy with desferrioxamine and deferiprone in iron overloaded thalassemia patients. Br J Hematol, 2003; 121:187–189.

 

Received on 21.12.2019            Modified on 25.02.2020

Accepted on 11.04.2020         © RJPT All right reserved