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Drug Review

Indian Pediatrics 2007;44:603-607 

Deferasirox: The New Oral Iron Chelator

 

A.P. Dubey
S. Sudha
Ankit Parakh

 

From the Department of Pediatrics, Maulana Azad Medical College, New Delhi 110 002.

Correspondence to: Dr. A.P. Dubey, Professor and Head, Department of Pediatrics, Maulana Azad Medical College,
New Delhi 110 002. E-mail: [email protected]

 

Abstract

Deferasirox is a new tridentate oral iron chelator developed by computer remodeling recently approved by FDA for children above 2 years. Phase II/III trials have demonstrated similar efficacy to desferrioxamine and better chelation efficiency. Adverse events were minor and growth remained unaffected. Data on cardiac iron chelation is limited although some studies have shown it comparable to deferiprone. The benefit to risk profile of deferasirox is favorable. This promising new drug might decrease the burden of subcutaneous or intravenous infusion improving compliance and hence the life expectation in thalassemic patients.

Key words: Deferasirox, Iron chelator, Thalassemia

Life expectancy of thalassemics has improved in the last few years with regular blood transfusions. This hyper-transfusion leads to iron overload, secondary hemosiderosis and multiple organ damage. Cardiac complications remain the leading cause of mortality in transfusional iron overload(1). The focus of problem has hence shifted to better chelation therapy.

Since 1963 desferrioxamine has remained the "gold standard" iron chelator and shown to reduce iron-related morbidity and mortality(2). Unfortunately, compliance with subcutaneous infusions still remains a serious limiting factor in treatment success. Deferiprone, an oral iron chelator has been in use in India for almost 10 years. Although total iron excretion with deferiprone is somewhat less than with desferrioxamine, it has a better cardio protective effect(3). However, certain side effects like arthropathy etc. limit its use despite the ease of oral administration.

Deferasirox (ICL670), is the first oral iron chelator approved in USA by FDA in November 2005(4). It was developed by computer remodeling, after evaluating more than 700 chelators from various chemical classes and belongs to a new class of tridentate chelator, the bishydroxy-phenyltriazoles(5).

Mechanism of action of iron chelators

Ferric iron has six coordination sites, which need to be chelated completely to prevent the generation of free radicals. Chelators, such as desferrioxamine, which coordinate all six sites using a single molecule (hexadentate chelators), form a more stable iron-chelate complex than ligands, which require more than one molecule. Chelators such as deferiprone possess only two co-ordination sites (bidentate chelators) tend to dissociate from iron at low concentrations and can generate free radicals. Deferasirox belongs to a new class of tridentate iron chelator requiring two molecules to form a complete complex with ferric iron. Comparison of different iron chelators is shown in Table I.

TABLE I

Comparison of Iron Chelators  
  Desferrioxamine Deferiprone Deferasirox
Class Hexadentate Bidentate Tridentate
Iron binding efficiency 1:1 3:1 2:1
Route of Parenteral, usually SC Oral; thrice a day Oral, can be used as
administration
 
night time infusion 5-7
nights/week
  a single daily dose
 
Plasma half-life Short (minutes) Moderate  (< 2 hours) Long (8-16 hours)
Myocardial iron chelation Low High Data insufficient
Important side effects Local skin reactions at Common: Abdominal Transcient gastrointestinal
  infusion sites, auditory discomfort; arthropathy. events; skin rash; mild
  and retinal toxicity, Rare: Severe agranulo- increased creatinine
  skeletal changes,
growth retardation
cytosis  (< 1%)
 
(clinically insignificant)
 
Brand Name Desferal Kelfer Asurna (India); Exjade (other
countries)
Availability Available Available Licensed by FDA; will be
      shortly available in India
TABLE II

 Phase II/III Studies on Deferasirox
  Patient
population
Patient
No.
Study design
 
Primary
endpoint
Secondary
endpoint
Phase II
Porter, et al.(7) β-thalassemia and 184 Non-comparative Safety and tolerability  Efficacy
  other rare anemias*        
Vichinsky, et al.(8) Sickle cell disease 195 Open lable, randomized Safety and tolerability  Efficacy
Piga, et al.(9) β-thalassemia 71 adults Open lable, randomized Safety and tolerability  Efficacy
Piga, et al.(10) β-thalassemia 40 pediatric Open lable, randomized Safety and tolerability  Efficacy
Phase III
Cappellini, et al.(11) β-thalassemia 586 Open lable, randomized Maintenance or Safety,
    (97 patients   reduction of LIC tolerability,
    <16 years)     change in
          serum ferritin
* Included: Thalassemia: 85; Myleodysplastic syndrome 47; Diamond Blackfan anemia 28; Others 23.

Clinical studies

After phase I studies(6,7) demonstrating safety and efficacy, deferasirox was evaluated in large multi-centric clinical phase II trials(8-11) and phase III trials(12) in patients with transfusion-dependent anemias (β-thalassemia, Sickle cell disease, etc.). All three major trials(8,9,12) enrolled adult and pediatric patients and 46.7% of patients were <16 years of age. Major studies are summarized in Table II.

A multicenteric phase III study compared the iron chelation of deferasirox and desferri-oxamine(12). Patients randomized to receive desferrioxamine with liver iron content (LIC) values <7 mg Fe/g dry weight (dw) were permitted to remain on their pre-study doses, even if these doses were higher than those specified by the protocol, since these doses were deemed to be safe and effective. LIC, the primary outcome variable for the demonstration of non-inferiority to desferrioxamine, was assessed at baseline and after 12 months of therapy by liver biopsy. In some patients, noninvasive magnetic susceptometry by super-conducting quantum interference device (SQUID) was used. Serum ferritin was measured monthly.

Success was defined as maintenance or reduction in the LIC as per the baseline LIC. Treatment was for one year initially, to be followed by an extension phase. Non-inferiority was demonstrated in the group of patients (69%) who were allocated to the higher dose groups (deferasirox doses of 20 or 30 mg/kg and desferrioxamine dose of 35 mg/kg) with baseline LIC levels >7 mg Fe/g dw. Overall success rates for deferasirox and desferrioxamine as analyzed by biopsy and SQUID were comparable (58.6% vs. 58.9%), and the lower limit of the 95% confidence interval (–10.2%) was above the non-inferiority threshold of –15% specified. Statistically significant and similar reduction in LIC (–5.3 ± 8.0 mg Fe/g dw, p <0.001), serum ferritin levels and change in iron balance (defined as the ratio of iron excretion to iron intake) was observed in both arms in patients with LIC values >1 = 7 mg Fe/g dry weight. All parameters indicated an increase in patients receiving deferasirox 5 or 10 mg/kg; essentially unchanged in those receiving deferasirox 20 mg/kg; and reduced for those receiving 30 mg/kg of deferasirox.

Pooled data analysis revealed that the overall chelation efficiency (per cent iron excretion vs. theoretical iron binding capacity of chelator dose) of deferasirox was twice that desferrioxamine (27% vs. 13%)(13). There are no studies comparing deferasirox with either deferiprone alone or deferiprone with desferrioxamine combination.

Adverse reactions

According to the pooled thalassemia data most frequent adverse events (>10% of all patients) were abdominal pain 23.8%, pyrexia 23.3%, headache 19.7%, cough 19.0%, diarrhea 16.6%, vomiting 13.8%, rash 12.4%, nausea 11.9%, increased creatinine 11.6%. These symptoms were generally manageable with supportive measures and have rarely required the permanent discontinuation of therapy. Deafness, neurosensory deafness or hypoacusis were reported in 0.3% only. The adverse event profile was almost similar in children.

Serious adverse events related to the drugs were reported in 13(3.1%) and 1(0.3%) of those receiving deferasirox and desferrioxamine, respectively. Adverse events that led to discontinuations included abnormal liver function tests and drug-induced hepatitis, skin rash, glycosuria/proteinuria, Henoch Schonlein purpura, hyperactivity/insomnia, drug fever, and cataract. Drug related agranulo-cytosis, thrombocytopenia, effect on hematologic parameters or bone changes have not been reported. Growth and development remained unaffected.

Deferasirox and heart

Deferasirox can readily enter into cardiomyocytes and scavenges labile cell iron(14). It was as effective as deferiprone in removing stored cardiac iron in a gerbil animal model(15). In a clinical trial of 23 patients treated with deferasirox, myocardial T2* improved significantly from a pretreatment geometric mean of 18.0 ms to 23.1 ms (p = 0.013). There was no significant change in left ventricular ejection fraction before or after treatment over the same period. These studies suggest that once daily mono-therapy with deferasirox will be effective at improving myocardial T2* and by inference myo-cardial iron loading in a wide range of patients with transfusional iron overload(16).

Prescribing information

Indications and Usage

Chronic iron overload secondary to blood transfusions (transfusional hemosiderosis) in patients >2 years. Therapy should be started when a patient has evidence of chronic iron overload (serum ferritin consistently >1000 µg/L).

Dosage

The initial dose is 20 mg/kg orally once daily; doses calculated to the nearest whole tablet. Adjust the dose in increments of 5 or 10 mg/kg every 3 to 6 months based on serum ferritin trends. The maximum dose is 30 mg/kg/day since there is limited experience with doses above this level. Deferasirox should be completely dispersed in water, orange juice or apple juice and be taken empty stomach 30 minutes before a meal preferably at the same time every day. The tablets should not be chewed or swallowed whole. After swallowing the suspension, any residue should be resuspended in a small volume of the liquid and swallowed. An initial higher dose of 30 mg/kg might be considered for severely iron overload patients (e.g., serum ferritin> 2500 µg/L). It is supplied as 125, 250 and 500 mg tablets for oral suspension.

Monthly monitoring of serum ferritin is recommended and the dose adjusted accordingly every 3 to 6 months, in steps of 5 or 10 mg/kg. If the serum ferritin falls consistently <500 µg/L, consider temporary interruption.

Pharmacokinetics

Deferasirox exhibits linear kinetics. The bio-availability is approximately 70%. Peak plasma concentrations of deferasirox are achieved between 1-4 hours and the mean elimination half-life is 8-16 hours. Once-daily doses can be used. Deferasirox is almost exclusively bound to albumin (99%). Metabolism is by glucuronidation with subsequent bilary excretion(17). The parent and metabolites are primarily excreted in the feces and minimally excreted renally (<8%). No significant drug interactions have been identified. Although studies in rats have shown a favorable interaction between desferrioxamine and deferasirox manifesting as improved chelating efficiency of deferaxirox, it should not be combined with other iron chelators, as safety of such combinations has not been established(18).

Contraindications

Use is contraindicated in patients with hyper-sensitivity to deferasirox.

Special populations

Renal dysfunction

Studies of deferasirox did not enroll patients with serum creatinine values above the upper limit of normal. Therefore, specific studies assessing deferasirox pharmacokinetics in renal impairment were not done. Dose-dependent increase in serum creatinine was observed in 38% cases. Most of the creatinine elevations remained within the normal range. After dose reductions (13% of cases) creatinine either returned to baseline or remained stable.

Hepatic dysfunction

Thalassemia patients with iron over1oad often have abnormal liver function tests due either to iron overload or concomitant viral hepatitis. Patients with mild to moderate elevations in serum transaminase levels (up to 5 times the upper limit of normal) were enrolled in the clinical studies and were treated with doses of deferasirox similar to patients without hepatic impairment. Safety, efficacy, and pharmacokinetic parameters were similar in both groups. The values showed marked fluctuations and were not progressive. Monthly laboratory monitoring of renal and hepatic function should be performed.

Special Senses

Auditory disturbances (high frequency hearing loss, decreased hearing), and ocular disturbances (lens opacities, cataracts, elevations in intraocular pressure, and retinal disorders) have been reported at a frequency of <1%. Auditory and ophthalmic testing (including slit lamp examinations and dilated fundoscopy) is recommended before starting treatment and thereafter at regular intervals (every 12 months). If disturbances are noted, dose reduction or interruption should be considered.

Pregnancy

Although animal studies have not shown any evidence of impaired fertility or harm to the fetus, there are no adequate and well-controlled studies in pregnant women.

Nursing mothers

Since it is not known whether deferasirox is excreted in human milk, caution should be exercised while administering to nursing mothers.

Cost analysis

There is no data on the cost benefit analysis using either deferiprone alone or deferiprone with desferrioxamine combination. There are no costing models available in the Indian context.

Conclusions

The benefit to risk profile of deferasirox is favorable. It has similar efficacy to desferrioxamine but is not associated with any significant complications. The cost effectiveness was favorable in costing models. This promising new oral drug will decrease the burden of subcutaneous or intravenous infusion, which might improve compliance and hence the life expectation.

Contributors: APD conceptualized the idea, edited and approved the final version. He will act as guarantor. SS and AP contributed towards literature search. AP prepared the manuscript.

What this Study Adds


• Deferasirox, a new oral iron chelator approved for children above 2 years, would be available soon in India.

• Phase II/III trials have demonstrated similar efficacy to desferrioxamine and better chelation efficiency with only few adverse events. The benefit to risk profile of deferasirox appears favorable but no Indian data is yet available.
 

 

 References

 

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2. Roberts DJ, Rees D, Howard J, Hyde C, Alderson P, Brunskill S. Desferrioxamine mesylate for managing transfusional iron overload in people with transfusion-dependent thalassemia. Cochrane Database Syst Rev. 2005; 19: CD004450.

3. Borgna-Pignatti C, Cappellini MD, De Stefano P, Del Vecchio GC, Forni GL, Gamberini MR, et al. Cardiac morbidity and mortality in deferoxamine - or deferiprone-treated patients with thalassemia major. Blood 2006; 107: 3733-3737.

4. Oral drug for iron overload. FDA Consum 2006; 40: 5.

5. Nick H, Acklin P, Lattmann R, Buehlmayer P, Hauffe S, Schupp J, Alberti D. Development of tridentate iron chelators: from desferrithiocin to ICL670. Curr Med Chern 2003; 10: 1065-1076.

6. Galanello R, Piga A, Alberti O, Rouan MC, Bigler H, Sechaud R, et al. Safety, tolerability and pharmacokinetics of ICL 670, a new orally active ironchelating agent in patients with transfusion-dependent ironoverload due to beta thalassemia. J Clin Pharmacol 2003; 43: 565-572.

7. Nisbet-Brown E, Olivieri NF, Giardina PJ, Grady RW, Neufeld EJ, Sechaud R, et al. Effectiveness and safety of ICL670 in iron-loaded patients with thalassaemia: a randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet 2003; 361: 1597-1602.

8. Porter J, Vichinsky E, Rose C, Piga A, Olivieri N, Gattermann N, et al. A Phase II Study with ICL670 (Exjadeâ), a Once-Daily Oral Iron Chelator, in Patients with Various Transfusion-Dependent Anemias and Iron Overload. Blood 2004; 104: 872A.

9. Vichinsky E, Fischer R, Fung E, Onyekwere O, Porter J, Swerdlow P, et a1. A randomized, controlled phase II trial in sickle cell disease patients with chronic iron overload demonstrates that the once-daily oral iron chelator deferasirox (Exjadeâ ICL670) is well tolerated and reduces iron. Blood 2005; 106: 95A.

10. Piga A, Galanello R, Cappellini MO, Forni GL, Lupo G, Ford JM, et al. Phase II study of ICL670, an oral chelator, in adult thalassaemia patients with transfusional iron overload: Efficacy, safety, pharmaco kinetics (PK) and pharmacodynamics (PD) after 18 months of therapy. Blood 2003; 102: 121A.

11. Piga A, Galanello R, Foschini ML, Zappu A, Bordone E, Longo F, et al. Once-daily treatment with the oral iron chelator ICL670 (Exjade ®): Results of a phase II study in pediatric patients with beta thalassemia major. Blood 2004; 104: 983A.

12. Cappellini MD, Cohen A, Piga A, Bejaoui M, Perrotta S, Agaoglu L, et al. A Phase III study of deferasirox (ICL670), a once-daily oral iron chelator, in patients with {beta}- thalassemia. Blood 2006; 107: 3455-3462.

13. Porter J, Borgna-Pignatti C, Baccarani M, Saviano A, Abish S, Malizia R, et al. Iron chelation efficiency of deferasirox (Exjadeâ, ICL670) in patients with transfusional hemosiderosis. Blood 2005; 106: 755A.

14. Cabantchik ZI, Link G, Glickstein H, Ben R, Hershko C, Konijn AM, Nick H. Deferasirox (Exjadeâ, ICL670): A Journey into Labile Iron Centers of Living Cardiomyocytes. Blood 2005; 106: 824A.

15. Wood JC, Duessel MO, Gonzales I, Aguilar M, Nick H, Shimada H, et al. ICL670 Removes Cardiac Iron in a Gerbil Model of Iron Overload. Blood 2005; 106: 2695A.

16. Porter JB, Tanner MA, Pennell DJ, Eleftheriou P. Improved myocardial T2* in transfusion dependent anemias receiving ICL670 (deferasirox). Blood 2005; 106: 1003A.

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18. Link G, Konijn AM, Breuer W, Cabantchik ZI, Hershko C. Exploring the "iron shuttle" hypothesis in chelation therapy: effects of combined deferoxamine and deferiprone treatment in hypertransfused rats with labeled iron stores and in iron-loaded rat heart cells in culture. J Lab Clin Med 2001; 138: 130-138.

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