Oral Iron Chelators: A New Avenue for the Management of ...

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Apr 16, 2010 - ABSTRACT. Removal of iron excess is the core of the treatment of iron overload caused by multiple transfusions for thalassemia syndrome.
Journal of Current Pharmaceutical Research 2010; 01: 1-7

JCPR 2010; 01:1-7 © 2010 Medipoeia Received: 16/03/2010 Revised: 16/04/2010 Accepted: 19/04/2010

Oral Iron Chelators: A New Avenue for the Management of Thalassemia Major Ritesh N. Sharma and S. S. Pancholi

Ritesh N. Sharma and S. S. Pancholi S. K. Patel College of Pharmaceutical Education and Research, Ganpat University, Mehsana-Gozaria Highway, Kherva –382 711, Gujarat, India

ABSTRACT Removal of iron excess is the core of the treatment of iron overload caused by multiple transfusions for thalassemia syndrome. Chronically transfused patients develop overload that leads to organ damage and ultimately to death. This review deals with the advances in iron chelating therapy. Regular subcutaneous administration of deferoxamine has dramatically altered the prognosis of thalassemia major and is considered the standard iron chelation therapy at present. Deferiprone is a first orally active iron chelator to reduce body iron to concentrations compatible with the avoidance of complications from iron over loading patients with thalassemia. Another chemical agent has recently been developed as oral active iron chelator; ICL-670 (Deferasirox) for the treatment of iron overload. It is tridentate oral iron chelator having low molecular weight with high selectivity and specificity for iron. The oral iron chelation therapy is the demand of present scenario to fight against the thalassemia major. Keywords: Thalassemia, Transfusion, Oral iron chelation

1. INTRODUCTION

Correspondence: Ritesh N. Sharma S. K. Patel College of Pharmaceutical Education and Research, Ganpat University, Mehsana-Gozaria Highway, Kherva –382 711, Gujarat, India E-mail: [email protected] Tel. No.: +91-2762 286082

In patients with thalassemia major, a regular program of transfusion sustains growth and development during childhood, but without iron chelation therapy, iron with in the transfused red blood cells accumulates inevitably (Cohen et al. 1987). Regular red blood cell (RBC) transfusion eliminate the complications of anemia and compensatory bone marrow (BM) expansion, permit normal development throughout childhood, and extend survival. In Chronic anemia associated with iron overload, iron-chelating therapy is the only method available for preventing early death caused mainly by myocardial and hepatic iron toxicity. Although Desferrioxamine (DFO) has been available for treating transfusional iron overload from the early 1960s but the era of modern and advance iron chelating therapy started only 20 years ago. Deferiprone (L1) is an orally active iron chelator mainly excreted via urine. Deferiprone binds iron in a 3:1 ratio at pH 7.4 (Hoffbrand et al. 1998). A new orally active iron chelator Deferasirox (ICL-670) with high iron binding potency and selectivity (Hershko et al. 1998). Today, long term DFO therapy is an integral part of management of thalassemia and other transfusion-dependent anemia, with a major impact on well-being and survival (Hershko et al. 2000). In untransfused patients with severe ß-thalassemia, abnormally regulated iron absorption results in increases in body iron burden that may, depending on the severity of erythroid expansion, vary between 2 and 5 grams per year. Regular transfusions may double this rate of iron accumulation. After approximately one year of transfusions, iron is deposited in parenchymal tissues, where it may cause significant toxicity as compared to that within reticuloendothelial cells. As iron loading progresses, the capacity of serum transferrin, the main transport protein of iron, to bind and detoxify iron may be exceeded.

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Thereafter, the non-transferrin-bound fraction of iron within plasma may promote generation of free hydroxyl radicals, propagators of oxygen-related damage (Hershko et al. 1998). The effectiveness of an iron-chelating agent depends in part on its ability to bind non-transferrin bound plasma iron over sustained periods of time, thereby ameliorating iron-catalyzed toxicity of free radicals. In this review we present the different type of oral iron chelators used in iron overload including their properties and other important data.

The most common endocrine abnormalities in patients with thalassemia in the modern era include hypogonadotropic hypogonadism, growth hormone deficiency, and diabetes mellitus. Variable incidences of hypothyroidism, hypoparathyrodism, and low levels of adrenal androgen secretion with normal glucocorticoid reserve, have been less commonly reported. Although normal rates of prepubertal linear growth may be observed in patients maintained on regular transfusion programs, poor pubertal growth and impaired sexual maturation have been observed in well-transfused patients.

2. CAUSES OF IRON OVERLOAD

Primary iron overload is caused by genetic disorders that create an imbalance in iron metabolism. Secondary iron overload is caused by factors that bypass normal iron homeostasis, such as repeated blood transfusion or acute or chronic iron poisoning. Iron overload may be treated or prevented with a chelating agent capable of complexion with iron and promoting its excretion.

Diabetes mellitus Diabetes mellitus in thalassemia has been attributed to impaired secretion of insulin secondary to chronic pancreatic iron overload (Lassman et. al. 1974 & Costin et. al. 1977) and to insulin resistance (Soudek et. al. 1979 & Zuppinger et. al. 1995) as a consequence of iron deposition within liver or skeletal muscle. Diabetes has also been linked temporally to episodes of acute viral hepatitis in some patients (Dmochowski et. al.1993) In most studies there exists a direct relationship between the development of diabetes and the severity and duration of iron overload (CavelloPerin et. al. 1995 & Olivieri et. al. 1990 ). The only iron-chelating agents are presently available for clinical use in thalassemia major.

Complications of iron overload in thalassemia major

3. IRON CHELATORS

The Heart

Chelators are small molecules that bind very tightly to metal ions. Some chelators are simple molecules that are easily manufactured (e.g., ethylene diamine tetra acetic acid; EDTA). Others are complex proteins made by living organisms (e.g., transferrin). The key property shared by all chelators is that the metal ion bound to the chelator is chemically inert. One key clinical feature of iron chelators is the degree to which they are absorbed from the gastrointestinal tract. A clinically highly effective iron chelator such as desferrioxamine has the drawback of very poor absorption from the gastrointestinal tract (Popper et.al. 1977). Consequently the drug must be given parenterally, as a continuous subcutaneous infusion, or as a continuous intravenous infusion (Cohen et.al. 1989 & Berati et.al. 1989). The expensive medical paraphernalia required for desferrioxamine administration makes the treatment expensive, and curbs its availability in areas of the world where medical resources are limited. Even when the resources exist to support iron chelation with desferrioxamine, the intrusiveness of pumps and other paraphernalia often impedes patient compliance (Liu et.al. 2002). For these reasons, an intensive search for orally active iron chelators is being conducted by a number of medical researchers. Over the last two decades, research efforts in the field of iron chelation have been directed towards the development of an oral chelator that would liberate thalassemic patients from daily continuous infusions of deferoxamine. Although many chelators have been identified, only a few have demonstrated a satisfactory oral bioavailability (Olivieri

Iron toxicity may damage the liver, heart and endocrine glands leading to debilitating and life-threatening problems such as diabetes, heart failure, and poor growth (Andrews et al. 1999 & Porter et al. 2001). Iron overload can result from either primary or secondary causes (Kirking et al. 1991).

The most frequent causes of death are still heart failure and/or cardiac arrhythmia, which are mostly caused by myocardial iron overload. The second cause is undercurrent infections. Most likely the most prevalent were overwhelming infections by encapsulated bacteria due to splenectomy, and Yersinia enterocolitis septicemia related to desferoxamine treatment. Within the heart, even small amounts of unbound iron may generate reactive harmful oxygen metabolites and toxicity, while both chronic pulmonary hypertension and myocarditis (Grisaru et al. 1990 & Kermastions et al. 1995). The Liver The liver is a major repository of transfused iron. Hepatic parenchymal iron accumulation, demonstrated after only 2 years of transfusion therapy, may rapidly result in portal fibrosis in a significant percentage of patients: one center has observed portal fibrosis in a high percentage of biopsies in children under the age of 3 years (Pierno et. al. 1992). In young adults with thalassemia major, in whom liver disease remains a common cause of death, viral infection (Sher et. al. 1993 & Tsukamoto et. al. 1995) and alcohol ingestion (Hoffbrand et. al. 1979) may act synergistically with iron in accelerating the development of liver damage. Endocrine glands

2

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et.al. 1997). At present, the two most interesting oral chelators are deferiprone and ICL670A are use in the treatment of iron overload. Comparison of different ion-chelator used in the therapy is given in table1.

stability for iron (III) reflected by the high pM value of 27.7 (Borgna et al. 1995). In 1995, Borgna-Pignatti and cohen first demonstrated in thalassemic patients that the 48h DFO induced urinary iron excretion after twice-daily subcutaneous bolus injections of desferrioxamine is similar to that after continuous infusion (Summers et al. 1979).

Table 1. Comparison of different iron chelators used in therapy

Characteristics

Desferrioxamine

Deferiprone

Deferasirox

Administration rout Half-life Routes of excretion Dose range Monitoring therapy

SQ, IV 20 minutes Urine/Stool 20-60 mg/kg/d

PO 2 to 3 hours Urine 50-100 mg/kg/d

PO 8 to 16 hours Stool 20-30 mg/kg/d

-Audiometry and eye exams annually -Serum ferritin level quarterly -Assessment of liver iron annually -Assessment of cardiac iron annually after 10 years of age

-CBC with differential weekly -ALT level monthly for first 3-6 months, then every 6 months -Serum ferritin level quarterly -Assessment of liver iron annually -Assessment of cardiac iron annually after 10 years of age

-Serum creatinine level monthly -ALT level monthly -Serum ferritin level monthly -Assessment of liver iron annually -Assessment of cardiac iron annually after 10 years of age

Advantage

-Long-term experience -Effective in maintaining normal iron stores -Reversal of cardiac disease with intensive therapy -May be combined with deferiprone

-Orally active -Safety profile well established -Enhanced removal of cardiac iron -May be combined with deferoxamine

-Orally active -Once daily administration -Demonstrated equivalency to deferoxamine at higher doses -Trials in several hematologic disorders

-Requires parenteral infusion -Ear, eye, bone toxicity -Poor compliance

-May not achieve negative iron balance in all patients at 75 mg/kg/day -Risk of agranulocytosis and need for weekly blood counts

-Limited longterm data -Need to monitor renal function -May not achieve negative iron balance in all patients at highest recommended dose

Disadvantage

O H2N

N OH

OH N O

OH N O

O

O N OH

N CH3 OH

Fig. 1. Deferoxamine (Hexadentate (1:1) High MW) Detailed pharmacokinetic knowledge lagged behind observations of the efficacy of prolonged infusions, but it became clear that the short plasma half-life together with the finite transiently chelatable iron pools favored a chelation regimen where the drug was delivered over a prolonged period. Early studies examined both IV bolus injections at 10 mg/kg and 24 hour continuous IV infusions at 100 mg/kg (Cohen et al. 2000). Peak plasma concentrations of 80-130 µM were obtained following the IV bolus with an initial half life of 5-10 minutes. The proportion and maximal plasma concentration of iron bound DFO (desferrioxamine) was higher in iron overloaded patients than in healthy volunteers. Steady state ferrioxamine (FO) concentrations with IV infusion at 100 mg/kg were also higher in iron-loaded subjects, 12.9 µM, than in controls, 2.7 µM. The clearance of FO, injected as (Lee et al. 1993) ferrioxamine, was found to be slow. Later studies using IV DFO and high performance liquid chromatography (HPLC) analysis showed that elimination from plasma has two components, with an initial half-life of 0.3 hour and a terminal half-life of 3 hours (Popper et al. 1977). Subcutaneous infusion at a daily dose 40 mg/kg over 8-12 hours has become the standard schedule of delivery for over 20 years (Hussain et al. 1976 & Hoyes et al. 1993). DFO is hydrophilic in nature, and this property together with its high molecular weight means that uptake into cells and subcellular compartments is generally slow relative to hydroxypyridinones taking several hours for equilibration (Olivieri et al. 1997). The very demanding nature of this therapy, from the patient’s point of view, has led researchers to investigate both new techniques for administration (twice daily subcutaneous bolus injection) and deferoxamine derivatives (HES-deferoxamine, deferoxamine depot) which can be infused over shorter periods. Hydroxyethyl starch deferoxamine is high molecular weight chelator has been obtained by binding hydroxyethyl starch polymer (HES) to deferoxamine (Olivieri et al. 1996). This molecule has the same affinity for iron as deferoxamine but its plasma half-life is 10-30 times longer (Olivieri et al. 1986). Deferoxamine-depot (ICL749B) is a new salt derived from the modification of deferoxamine, which is then suspended in a lipid carrier for slow release. This formulation, which can be administered by

Desferrioxamine Desferrioxamine mesylate (Desferal, Novartis), a trihydroxamic acid produced by Streptomyces pylosus, is capable of complexing with iron and promoting fecal and urinary excretion (Olivieri et al. 1999). Owing to its poor absorption from the gastrointestinal tract and its rapid metabolism in plasma, desferrioxamine is usually administered by prolonged parenteral infusion through a portable pump (Raymond et.al. 1981). The advantage of this hexadentate structure is the relatively high 3

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subcutaneous injection, is active for about 30 hours thus reducing the volume and administration time of the chelating drug. Toxicity from DFO in thalassemia major is unlikely provided that doses should not exceed 40 mg/kg/day, that DFO is not introduced at too young an age and that the dose is reduced as iron loading falls. In other conditions where iron overload and distribution may be difficult to determine, such as sickle cell disorders, particular caution with dosing and monitoring is advisable. Symptoms include this deferoxamine is blurred vision, loss of central vision, night blindness and optic neuropathy (Arden et al. 1984). The risk may be higher in patients with diabetes or other factors affecting the blood-retinal barrier (Robbins et al. 1982), so these groups should be monitored more carefully. Symptoms and electroretinographic disturbances generally resolve over 1-2 months of stopping treatment provided these are identified sufficiently quickly. Failure to do so can lead to permanent retinal damage. Local reactions with skin reddening and soreness occurring immediately or after the infusion can be seen at the subcutaneous infusion site. There is an increased risk of Yersinia infection in iron overload, and this risk increases further with DFO treatment as Yersinia does not make a natural siderophore and uses iron from FO to facilitate its growth (Robbins et al. 1985). In addition, it is an excellent tool for improving patient’s compliance allowing uninterrupted delivery of DFO and the effective depletion of very large iron stores.

account for its rapid absorption from the gut. These same properties also allow more rapid access by deferiprone and related HPOs to intracellular iron (Zanninelli et al. 1997) to labile intracellular iron (Hoffbrand et. al. 1998) maximum serum concentrations were observed within 12 minutes to 2 hours after oral intake (Olivieri et al. 1995) The quantity of iron excreted by deferiprone is related to three main factors: a) dose, b) frequency of administration and c) iron load of the patient. In general, the higher these factors, the more iron is excreted (Addis et al. 1999). A metaanalysis (Kontoghiorghes et al. 1990) of the main deferiprone clinical trials between 1989 and 1999 concluded that this drug, at a dose of at least 75 mg/kg/day, is clinically effective in inducing a negative iron balance and reducing the body iron burden in most patients with marked iron overload. Deferiprone appears in plasma within 5 to 10 minutes of ingestion, the peak concentrations (Cmax) occurring within 1 hour, reaching levels in excess of 300 µM after oral ingestion of a 50 mg/kg dose (al- Refaie et al. 1995 & Lange et al. 1993). Deferiprone is metabolized to the inactive glucuronide that is the predominant form recovered in the urine (Kontoghiorghes et al. 1990). The peak concentration of the glucuronide typically occurs about 30 minutes after the peak of the native compound. The side effects of deferiprone therapy include arthropathy, abnormalities of liver function, gastrointestinal disturbances, mild neutropenia and agranulocytosis. Deferiprone seems to be highly selective for iron, a fact that leads to no considerable excretion of most biologically important trace elements namely: calcium, magnesium, copper, aluminum (Olivieri et al. 1995).

Deferiprone (1, 2-dimethyl1-3-hydroxypyrid-4-one) Deferiprone (Ferriprox®), also known as L1, is an orally active iron chelator that has been studied extensively in clinical trials. In spite of the proven efficacy of DFO, not all patients are willing to cope with the rigorous requirements of the long terms use of portable pumps. In view of these considerations, there is a great need for the development of alternative, orally effective iron chelating drugs. Deferiprone (1,2 dimethy-3-hydroxypyridin-4one) is a member of a family of hydroxypyridin-4-one (HPO) chelators (Porter et al. 1988) that require three molecules fully to bind iron (III), each molecule providing two co-ordination sites (bidentate chelation). The pM of deferiprone for iron (III) (pM = 20) is less than that of DFO, which reflects the lower stability of

The adverse effects have been seen i.e. musculoskeletal pain and arthralgia (35%), gastric intolerance (20%), agranulocytosis (1-2%) and zinc deficiency (1%). Withdrawal of therapy led to resolution of these symptoms (Hershko et al. 1998, Hoffbrand et. al. 1995 & Agarwal et al. 1992). Painful swelling of the joints, particularly the knees also occurs in 6-39% of patients (Cohen et al. 2000, al- Refaie et. al. 1992 & al-Refaie et. al. 1995). This complication occurs usually but not always resolves after stopping therapy. Other unwanted effects include nausea (8%), zinc deficiency (14%) and fluctuation in liver function tests (44%) (Wonke et al.1998). Deferiprone may have serious side effects, including agranulocytosis, neutropenia, arthropathy, gastrointestinal disorders, and zinc deficiency. The relevance of metabolism and plasma concentrations of deferiprone to agranulocytosis is under investigation but is presently unclear. It is known that whether increasing the dose of L1 from 75 mg/kg/day to 100 mg/kg/day, as has been advocated for patients whose liver iron concentrations fail to respond (Castriota-Scanderbeg et al. 1997), will increase the risk of agranulocytosis, In some patients an immune mechanism may be involved, as suggested by a report of agranulocytosis associated with a vasculitic syndrome and disturbances of immune function (Grady et al. 1996). The failure to achieve a steady decrease in storage iron with L1 is explained by the difference in efficacy between the two drugs on a weight per weight basis. On the basis of metabolic balance study comparing

O OH N OH CH3 Fig. 2. Deferiprone (Bidentate (3:1) Low MW) the iron-chelate complex. The molecular weight of deferiprone is approximately one-third that of DFO. Low molecular weight together with its neutral charge and relative lipophilicity; 4

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combined urinary and fecal iron excretion in thalassemic patients receiving either 60-mg\kg DFO or 75 mg\kg PO L1, mean iron excretion on L1 was only 65% of that then DFO (Heinz et al. 1999). However, in some patients L1 was as or more effective, than DFO.

a “shuttle effect” i.e. ICL-670 working as an intracellular chelator and DFO as a powerful extra-cellular chelator. In addition, combination therapies have been looked upon as the most promising once. They are expected to produce synergistic effect leading to enhanced iron excretion from target specific iron compartments, less side-effects, improved compliance and individualization of therapy. Better kinetics of iron metabolism, iron overload and chelation would help in improving these innovative therapeutic strategies.

Deferasirox (ICL670) Deferasirox (Exjade®, ICL670) is an oral chelator with high ironbinding potency and selectivity. It is an N-substituted bishydroxyphenyl-triazole (Nick et al. 2003) that was selected from more than 700 compounds as part of a rational drug development program. It represents a new class of tridentate iron chelators with a high specificity for iron (Hershko et al. 1998). Two molecules of the chelator are required to form a complete complex with ferric iron. It is chelated to both from the reticulo-endothelial cells (RE cells) as well as various parenchymal organs and the chelated iron is cleared by the liver and excreted through the bile. The binding ratio of this ICL-670 is 2:1. It also has the ability to prevent myocardial cell iron update. It is four to five times more effective than parenteral desferrioxamine in promoting the excretion, which is predominantly via the fecal route, of chelatable iron from hepatocellular iron stores (Hershko et al. 2001). These unique chelating properties of ICL670A may have practical implications for current efforts to design better therapeutic strategies for the management of transfusional iron overload. In animal models, on molar basis, it has been shown to be 5 times more potent than DFO (hexadentate) and 10 times more potent than deferiprone (bidentate) (Grady et al. 2002).

3. FUTURE PERSPECTIVE A future perspective in the traditional management of thalassemia major is obviously the introduction of new types of iron chelation therapy that are more efficient and more acceptable to patients. Promising results are expected from the use of the combination of deferiprone and desferal (Wonke et al. 1999) which appear to have a synergistic effect and possibly a better activity on removal of iron from the heart (related to deferiprone) (Anderson et. al. 2002), as well as the development of new iron chelators, some of which (ICL 670 and GT56-252) seem to have interesting properties and activities (Galanello et al. 2003 & Donovan et al.2004). 4. CONCLUSION Research efforts in the field of chelation therapy have been directed in the last few years towards the production of a safe and effective orally active iron chelator. Iron-chelating therapy with in patients with thalassemia major has dramatically altered the prognosis of this previously fatal disease. The successes achieved with conventional therapy, as well as the limitations of the treatment have stimulated the design of alternative strategies of iron-chelating therapy, Safe and effective orally active iron chelation remains a high priority for the development of earlier iron chelation therapy. The oral iron chelator i.e. Deferiprone and Deferasirox (ICL670) gaining popularity, had already been discussed in the review. Careful controlled studies of the risks and benefits of any new therapy are required before widespread implementation of new therapies. Such development and the evolution of improved strategies of this therapy require better understanding of the pathophysiology of iron toxicity and the mechanism of action of iron chelating drugs.

OH O

N N N OH

HO

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Fig. 3. Deferasirox (ICL 670) (Tridentate (2:1) Low MW)

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