oral iron chelator.pdf

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Journal of Current Pharmaceutical Research 2010; 01: 1-7

JCPR 2010; 01:1-7 2010 Medipoeia

Received: 16/03/2010

Revised: 16/04/2010Accepted: 19/04/2010

Ritesh N. Sharma and S. S. PancholiS. K. Patel College of Pharmaceutical

Education and Research, Ganpat

University, Mehsana-Gozaria Highway,

Kherva 382 711, Gujarat, India

Correspondence:

Ritesh N. SharmaS. K. Patel College of PharmaceuticalEducation and Research, Ganpat

University, Mehsana-Gozaria Highway,

Kherva 382 711, Gujarat, IndiaE-mail: [email protected]

Tel. No.: +91-2762 286082

Oral Iron Chelators: A New Avenue for the

Management of Thalassemia Major

Ritesh N. Sharma and S. S. Pancholi

ABSTRACT

Removal of iron excess is the core of the treatment of iron overload caused by multipletransfusions 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 chelatingtherapy. 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. Anotherchemical 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 withhigh selectivity and specificity for iron. The oral iron chelation therapy is the demand of presentscenario to fight against the thalassemia major.

Keywords:Thalassemia, Transfusion, Oral iron chelation

1. INTRODUCTION

In patients with thalassemia major, a regular program of transfusionsustains growth and

development during childhood, but withoutiron 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 -thalassemia, abnormally

regulated iron absorption results in increases inbody iron burden that may, depending on the

severity of erythroidexpansion, vary between 2 and 5 grams per year. Regular transfusions

may double this rate of iron accumulation. After

approximately one year of transfusions, ironis 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 maintransport 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 bindnon-transferrin bound plasma iron over sustained

periods oftime, 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.

2. CAUSES OF IRON OVERLOAD

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).

Primary iron overload is caused by genetic disorders

that create an imbalance in iron metabolism. Secondary iron

overloadis 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 agentcapable of complexion with iron and promoting its

excretion.

Complications of iron overload in thalassemia major

The Heart

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

enterocolitissepticemia 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 Li ver

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.

Endocri ne glands

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.

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 (Cavello-

Perin et. al. 1995 & Olivieri et. al. 1990 ).

The only iron-chelating agents are presently available for clinical

use in thalassemia major.

3. IRON CHELATORS

Chelators are small molecules that bind very tightly tometal 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 intravenousinfusion (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

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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.

Table 1. Comparison of different iron chelators used in therapy

Characteristics Desferrioxamine Deferiprone Deferasirox

Administration

rout

Half-life

Routes of

excretion

Dose range

SQ, IV

20 minutesUrine/Stool

20-60 mg/kg/d

PO

2 to 3 hoursUrine

50-100 mg/kg/d

PO

8 to 16 hoursStool

20-30 mg/kg/d

Monitoring

therapy

-Audiometry and

eye exams

annually-Serum ferritin

level quarterly-Assessment of

liver iron annually

-Assessment of

cardiac iron

annually after 10years of age

-CBC with

differential

weekly-ALT level

monthly for first3-6 months, then

every 6 months

-Serum ferritin

level quarterly

-Assessment ofliver iron

annually

-Assessment ofcardiac iron

annually after 10

years of age

-Serum creatinine

level monthly

-ALT levelmonthly

-Serum ferritinlevel monthly

-Assessment of

liver iron annually

-Assessment of

cardiac ironannually after 10

years of age

Advantage -Long-term

experience-Effective in

maintaining normal

iron stores

-Reversal ofcardiac disease

with intensive

therapy-May be combined

with deferiprone

-Orally active

-Safety profilewell established

-Enhanced

removal of

cardiac iron-May be

combined with

deferoxamine

-Orally active

-Once dailyadministration

-Demonstrated

equivalency to

deferoxamine athigher doses

-Trials in several

hematologicdisorders

Disadvantage -Requires

parenteral infusion

-Ear, eye, bonetoxicity

-Poor compliance

-May not achieve

negative iron

balance in allpatients at 75

mg/kg/day

-Risk ofagranulocytosis

and need for

weekly blood

counts

-Limited long-

term data

-Need to monitorrenal function

-May not achieve

negative ironbalance in all

patients at highest

recommended

dose

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

stabilityfor iron (III) reflected by the high pM value of 27.7

(Borgna et al. 1995). In 1995, Borgna-Pignatti and cohenfirst

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).

N N N

H2N N N CH3

O

O O

O O

OH

OH OH

OH OH

Fig. 1.Deferoxamine (Hexadentate (1:1) High MW)

Detailed pharmacokinetic knowledge lagged behind

observations of the efficacy of prolonged

infusions, but it becameclear that the short plasma half-life together with the finite

transiently chelatable iron pools favoreda chelation regimen where

the drug was delivered over a prolongedperiod. 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 M wereobtained following the

IV bolus with an initial half life of5-10 minutes. The proportion

and maximal plasma concentration

of iron bound DFO

(desferrioxamine) was higher in iron overloadedpatients 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 M, than in controls,2.7 M. The clearance of FO,

injected as (Lee et al. 1993)ferrioxamine,was found to be slow.

Laterstudies using IV DFO and high performance liquid

chromatography(HPLC) analysis showed that elimination from

plasma has twocomponents, with an initial half-life of 0.3 hour and

a terminalhalf-life of 3 hours (Popper et al. 1977). Subcutaneous

infusion at a daily dose 40 mg/kg over 8-12 hourshas 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 highmolecular weight means that uptake

into cells and subcellular compartments is generally slow relativeto hydroxypyridinones taking several hours for equilibration

(Olivieri et al. 1997). The very demanding nature of this therapy,

from the patients 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

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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 reducedas 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. Failureto do so can lead to permanent retinal

damage. Local reactions with skin reddening and soreness

occurringimmediately 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 Yersiniadoes 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 patients compliance

allowing uninterrupted delivery of DFO and the effective depletion

of very large iron stores.

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-4-

one) is a memberof 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 deferipronefor iron (III) (pM =

20) is less than that of DFO, which reflects the lower stability of

N

OH

OH

CH3

Fig. 2.Deferiprone (Bidentate (3:1) Low MW)

the iron-chelate complex. The molecular weight of

deferiprone is approximately one-thirdthat of DFO. Low molecular

weight together with its neutral charge and relativelipophilicity;

account for its rapid absorption from the gut. These same

properties also allow more rapid access by deferiproneand 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 meta-

analysis (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

M after oral ingestion of a 50mg/kg dose (al- Refaie et al. 1995 &

Lange et al. 1993). Deferiprone is metabolized to the inactive

glucuronide thatis the predominant form recovered in the urine

(Kontoghiorghes et al. 1990). The peak concentration of the

glucuronide typically occurs about 30 minutesafter 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).

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 butnot 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 zincdeficiency. 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 reportof

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

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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.

Deferasirox (ICL670)

Deferasirox (Exjade, ICL670) is an oral chelator with high iron-

binding potency and selectivity. It is an N-substituted bis-

hydroxyphenyl-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 ironis 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).

N

N

N

OH HO

O

OH

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

It is highly selective for iron and does not induce the

excretion of zinc or copper. It should be used to extend the scope

of iron chelating strategies in a manner analogous with the

combined use of medications in the management of other

conditions like hypertension and diabetes (Hershko et. al. 2002).

Combined use of DFO and L1 has already been shown to be

effective and convenient in patients previously failing to single

drug therapy (Pippard et. al. 1979).The combination may also have

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.

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) whichappear 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 theevolution of improved strategies of this therapy require better

understanding of the pathophysiology of iron toxicity and the

mechanism of action of iron chelating drugs.

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