Efficacy and safety of iron-chelation therapy with deferoxamine, deferiprone, and deferasirox for the treatment of iron-loaded patients with non-transfusion-dependent thalassemia syndromes

Figures & data

Figure 1 Structure of the chelating drugs.

Notes: The chemical and physicochemical properties of chelating drugs influence their clinical activity, including their mode of action, organ targeting, efficacy, and toxicity. Deferiprone and deferoxamine are hydrophilic chelators that increase iron excretion and decrease iron absorption. Maltol, deferasirox, and 8-hydroxyquinoline are lipophilic chelators that form lipophilic metal complexes, and can cause an increase in iron and other metal absorption. Orally absorbed, nonmetal-bound deferasirox mobilizes excess iron, mainly from the liver, and causes an increase in iron excretion. The pharmacological effects of different drugs, eg, hydroxycarbamide (hydroxyurea) are affected by iron binding.

Table 1 Examples of thalassemia intermedia and other conditions where iron overload can be caused from the increased gastrointestinal absorption of iron*

Thalassemia genotypes

β-Thalassemia

Heterozygous mild β^+/severe β^+

Homozygous β^0 or β^+ with genetic factors leading to increased

γ-chain production

Homozygous normal HbA2 β-thalassemia (type I)

Heterozygous β^0 or β^+/normal HbA2 β-thalassemia (type I)

Severe heterozygous β-thalassemia

δβ-thalassemia and high persistent fetal hemoglobin (HPFH)

Homozygous ^Gγ-, δβ-thalassemia

Heterozygous β^0- or β^+-thalassemia/δβ-thalassemia

Heterozygous Greek HPFH/β-thalassemia

β or δβ thalassemia with structural hemoglobin variants

Hb S, C, or E in association with β^0-, β^+-, or δβ-thalassemia

HbE thalassemia

HbE β-thalassemia

α-Thalassemia

Homozygous α (0 or − −/− −) hydrops fetalis

Heterozygous α (−−/−α) (HbH disease)

Heterozygous α (−−/αα)

Interactions of α- and β-thalassemia

Interactions of α-thalassemia and hemoglobin S

Other iron-loading conditions caused from increased iron absorption

Hereditary hemochromatosis

Related to the HFE gene. Not related to HFE gene.

Juvenile hemochromatosis

Neonatal hemochromatosis

Chronic anemias

Sideroblastic anemia. Congenital atransferrinemia

Exogenous iron overload

Oral iron supplements. Accidental iron poisoning

Chronic liver diseases

Viral hepatitis. Alcoholic liver disease. Nonalcoholic steatohepatitis

Porphyria cutanea tarda

Notes:

* Increased gastrointestinal iron absorption is observed in different thalassemia intermedia genotypes, hereditary hemochromatosis, and other conditions, which can lead to iron overload. The main diagnostic criteria for iron overload are increased serum ferritin and transferrin iron-saturation levels and decrease in the signal intensity of magnetic resonance imaging T₂ or T₂* in the liver and heart, due to excess iron accumulation and deposition.

Abbreviation: Hb, hemoglobin.

Figure 2 Iron-absorption and iron-overload mechanisms in non-transfusion-dependent thalassemias: the role of chelators and chelating drugs.

Notes: Mechanism of iron absorption at the enterocyte using regulatory pathways of iron metabolism involving DMT1, hepcidin, ferroportin, and transferrin. Increased gastrointestinal iron absorption and iron overload is observed in non-transfusion-dependent thalassemias, due to ineffective erythropoiesis in the bone marrow (A). The level of increased iron absorption depends on the form and quantity of iron present in the diet and other factors, such as the presence of natural or synthetic iron chelators in the gastrointestinal tract. Iron-chelating drugs and other chelators have variable pharmacological effects on iron absorption, with lipophilic chelators causing an increase in iron absorption and hydrophilic chelators a decrease in iron absorption. Excess iron absorption causes iron overload and damage in the liver, the heart, and other organs. The liver is the main organ of excess iron deposition, whereas the heart is the most susceptible organ of iron toxicity, as a result of iron overload from increased iron absorption. Iron overload in both the liver (B) and the heart (C) in non-transfusion-dependent thalassemia are the main target sites of chelation therapy.
Abbreviations: DMT1, divalent metal transporter 1; EDTA, ethylenediaminetetraacetic acid; DTPA, diethylenetriaminepentaacetic acid.

Table 2 Examples of nonregulatory factors affecting iron absorption*

Quantity of iron present in the diet, eg, vegetarian meals contain less iron

Quality of iron (ferrous, ferric, heme, ferritin, hemosiderin) in the diet

Presence of dietary reducing agents, eg, ascorbic acid

Presence of dietary molecules with chelating properties, eg, tannins and polyphenols

Presence of oral drugs with chelating properties, eg, tetracycline and hydroxycarbamide

The quantity of water, alcohol, and other fluid intake in the gastrointestinal tract

Drugs and dietary molecules affecting iron transport across the enterocyte (eg, nifedipine, which is an L-type calcium-channel blocker)

Dietary factors affecting the solubilization of iron pH of the stomach and intestine

Modulators of DMT1, hepcidin, ferroportin, and transferrin activity

Gastrectomy and other interventions where gastrointestinal function is affected

Infectious, inflammatory, chronic liver disease, and other diseases

Aging, sports

Exogenous iron supplementation

Chronic iron supplementation. Oral iron supplements. Use of iron cooking utensils

Notes:

* Many dietary, nonregulatory, and other factors such as those described in this table can affect the absorption of iron under normal conditions. The same and similar factors, as well as other regulatory factors, such as the erythropoietic activity of the bone marrow in thalassemia intermedia and other iron-loaded non-transfusion-dependent thalassemias where ineffective erythropoiesis is observed, can also affect the rate of iron absorption and can lead to variable levels of iron deposition and overload in the liver, the heart, and other organs of the affected patients.

Abbreviation: DMT1, divalent metal transporter 1.

Table 3 Mode of action and property differences of the chelating drugs deferoxamine, deferiprone, and deferasirox and other chelators*

Clinical and biological effects

Recommended doses of the chelating drugs in non-transfusion-depenent thalassemias

DFO subcutaneously or intravenously 10–60 mg/kg/day. Oral L1

10–100 mg/kg/day. Oral DFX 10–40 mg/kg/day. Combination of chelating drugs at different doses

Iron-loaded patient compliance with chelating drugs

Low compliance with DFO in comparison to oral L1and DFX

Effect of chelating drugs on iron absorption

Increase of iron absorption by the lipophilic chelators maltol,

8-hydroxyquinoline, and DFX. Decrease of iron absorption by the hydrophilic chelators DFO, EDTA, DTPA, and L1

Iron removal from diferric transferrin in iron-loaded patients

Removal of approximately 40% of iron at L1 concentrations >0.1 mM, but no removal of iron by DFO or DFX at even 4 mM concentrations

Differential iron removal from various organs of iron-loaded patients

Efficacy is related to dose for all chelators. L1 preferential iron removal from the heart and DFX from the liver. DFO iron removal from the liver and/or heart (especially following intravenous administration)

Iron redistribution in diseases of iron metabolism by chelating drugs

L1 and to a lesser extent DFO can cause iron redistribution from iron deposits and also through transferrin (only in the case of L1), eg, from the reticuloendothelial system to the erythron in the anemia of chronic disease. DFX may cause redistribution of iron from the liver to other organs in iron-loaded patients.

Enterohepatic circulation by DFX and DFX metabolites

Increase excretion of metals other than iron, eg, Zn and Al

DTPA > L1 > DFO (order of increased Zn excretion in iron-loaded patients)

DFO and L1 cause increased Al excretion in renal dialysis patients

DFX causes increases in Al and other toxic metal absorption

Iron mobilization and excretion of chelator metabolite iron complexes

Several DFO metabolites have iron-chelation potential and increase iron excretion, but not the L1 glucuronide or the DFX glucuronide metabolites

Combination chelation therapy

L1, DFO, and DFX combinations are more effective in iron excretion than monotherapy. The ICOC L1 and DFO combination protocol causes normalization of the iron stores in thalassemia major and IL-NTDT patients

Chelating drug synergism with reducing agents

Ascorbic acid acts synergistically with DFO but not with L1 or DFX for increasing iron excretion

Metabolism and pharmacokinetics

Metabolite(s)

DFO: a number of metabolites, including some with chelating properties, which are cleared mainly through the urine. L1 : the L1–glucuronide conjugate is cleared through the urine, but has no iron-chelation properties. DFX: the DFX–glucuronide conjugates are cleared through the feces and have no iron-chelation properties

t½ absorption following oral administration

L1 : 0.7–32 minutes. DFX: 1–2 hours

Tmax of the chelator

L1 : mostly within 1 hour. DFX: mostly 4–6 hours

t½ elimination of chelator

Intravenous DFO: 5–10 minutes. Oral L1 : 47–134 minutes at 35–71 mg/kg. Oral DFX: 19±6.5 hours at 20 and 40 mg/kg

t½ elimination of the iron complex

DFO: 90 minutes. L1 : estimated within 47–134 minutes. DFX: 17.2±7.8 hours at 20 mg/kg and 17.7±5.1 hours at 40 mg/kg

Tmax of the iron complex

L1 : estimated within 1 hour. DFX: 1–6 hours at 20 mg/kg and 4–8 hours at 40 mg/kg

Tmax of the metabolite

L1–glucuronide 1–3 hours

Route of elimination of chelator and its iron complex

DFO: urine and feces. L1 : urine. DFX: almost exclusively in feces, and less than 0.1%–8% in urine

Enterohepatic circulation

DFX and metabolites, but not DFO or L1

Chemical and physicochemical properties

Molecular weight of chelators (g/mole)

DFO: 561. L1 : 139. DFX: 373

Molecular weight of iron complexes (g/mole)

DFO: 617. L1 : 470. DFX: 798

Charge of chelators at pH 7.4

DFO: positive. L1 : neutral. DFX: negative

Charge of iron complexes at pH 7.4

DFO: positive. L1 neutral. DFX: negative

Partition coefficient of chelators (n-octanol/water)

DF: 0.02. L1 : 0.19. DFX: 6.3

Logβ of chelator iron complexes

DFO: 31. L1 : 35. DFX: 27

Notes:

* The clinical, biological, toxicological, and pharmacological effects of iron-chelating drugs and other chelators depend on their chemical and physicochemical properties, as well as the properties of their iron and other metal complexes, and also on their metabolites. There is wide variation in the mode of action of the three chelating drugs DFO, L₁, and DFX, including their efficacy in iron removal from different organs and also in the toxic side effects in iron-loaded patients, including IL-NTDT patients.

Abbreviations: DFO, deferoxamine; L₁, deferiprone; DFX, deferasirox; EDTA, ethylenediaminetetraacetic acid; DTPA, diethylenetriaminepentaacetic acid; ICOC, International Committee on Chelation; IL-NTDT, iron-loaded non-transfusion-dependent thalassemia.