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  • Drug Evaluation

    10.1517/14656560802335333 2008 Informa UK Ltd ISSN 1465-6566 2391All rights reserved: reproduction in whole or in part not permitted

    Long-term experience with deferasirox (ICL670), a once-daily oral iron chelator, in the treatment of transfusional iron overload MD Cappellini & A Taher University of Milan, Department of Internal Medicine, Policlinico Foundation IRCCS, Milan, Italy

    Background : Chronic iron overload from frequent blood transfusions to treat patients with severe anaemias leads to significant morbidity and mortality. While deferoxamine, the current standard of care, is an effective iron chelator, it requires subcutaneous infusion for 8 12 h/day, 5 7 days/week. This regimen is problematic and impacts significantly on patients daily life. Objective : To evaluate the efficacy and tolerability of deferasirox, a once-daily oral iron chelator. Method : To review the available data reported in peer-reviewed journals (using PubMed) and at medical conferences. Results/conclusions : Deferasirox is effective in reducing or maintaining iron burden in patients with transfusion-dependent anaemias. As deferasirox is orally administered, the inconvenience of parenteral administration with deferasirox is avoided. Deferasirox improves patient satisfaction and is expected to improve compliance with iron chelation therapy.

    Keywords: deferasirox , effective , Exjade , transfusional iron overload

    Expert Opin. Pharmacother. (2008) 9(13):2391-2402

    1. Introduction

    Chronic iron overload is the main complication resulting from regular blood transfusions used to treat severe, genetically based, haemolytic anaemias such as -thalassaemia and sickle cell disease (SCD), as well as rarer conditions causing anaemia such as myelodysplastic syndromes (MDSs). If left untreated, chronic iron overload causes significant damage to the heart, liver and endocrine glands and can lead to premature death [1,2] . It is widely accepted that, without adequate iron chelation therapy, patients with iron overload experience greater morbidity and mortality, as well as higher hospitalisation rates and medical care costs, than patients who are adequately chelated. More than half of all deaths in patients with -thalassaemia, for example, are attributable to cardiac complications as a result of inadequate iron chelation rather than the underlying disease [3] . Several studies have shown that reduction of body iron levels through chelation therapy provides significant benefits in patients with transfusional haemosiderosis [4-7] .

    While deferoxamine (DFO), the current reference standard of care in iron chelation, is an effective chelator, it requires subcutaneous infusion lasting 8 12 h per day, 5 7 days a week for as long as the patient continues to receive blood transfusions. This regimen is problematic for most patients, interfering significantly with their daily life and, subsequently, often resulting in poor patient compliance [8] . The introduction of the first oral chelator, three times daily deferiprone, seemed a promising step forward for the treatment of patients with transfusional iron overload. However, the use of deferiprone has been limited due

    1. Introduction

    2. Overview of the market

    3. Introduction to deferasirox

    4. Chemistry

    5. Pharmacokinetics and

    pharmacodynamics

    6. Clinical experience

    with deferasirox

    7. Safety and tolerability

    8. Regulatory affairs

    9. Conclusions

    10. Expert opinion

    11. Five-year view

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  • Deferasirox (ICL670)

    2392 Expert Opin. Pharmacother. (2008) 9(13)

    to the occurrence of serious adverse events during treatment, such as neutropenia and agranulocytosis [9,10] .

    Deferasirox (ICL670) is a novel, orally active iron chelator that provides effective 24 h chelation, 7 days per week, with one daily dose. An extensive clinical trial programme has demonstrated that deferasirox 20 30 mg/kg/day is as effective as DFO in reducing or maintaining iron burden in adult and paediatric patients ( 2 years) with a variety of transfusion-dependent anaemias, including -thalassaemia, SCD and MDS. Moreover, as deferasirox is orally active and dispersed in water or juice, the inconvenience of parenteral administration and disruption to daily life with DFO is avoided. It has also been shown that deferasirox is more cost-effective than deferoxamine, due to the cost and quality of life benefits derived from the more straightforward and convenient oral mode of administration [11] .

    Transfusions and iron chelation therapy have dramatically improved the quality of life for patients with severe anaemias. Previously a rapidly fatal disease in early childhood, -thalassaemia, for instance, is now a chronic disease compatible with prolonged life. Today, life expectancy varies between 25 and 55 years, depending on patient compliance with medical treatment, particularly iron chelation. Due to its oral formulation, deferasirox could be expected to improve patient satisfaction and compliance with iron chelation therapy and, ultimately, quality of life.

    2. Overview of the market

    Orally bioavailable chelators for transfusional iron overload have been sought since the introduction of DFO. Despite great effort, only deferiprone and deferasirox have successfully reached the market, reflecting the difficulty in combining oral activity and safety/tolerability. All currently available iron chelators require careful patient monitoring to ensure iron burden is being actively reduced within specific safety parameters. A brief summary of characteristics and established monitoring guidelines for DFO, deferiprone and deferasirox are presented in Table 1 .

    DFO is the current reference standard for iron chelation therapy and has been available in clinical practice for more than 40 years. Numerous studies have shown that iron-overloaded patients who receive regular chelation therapy with DFO experience substantial clinical benefits due to a reduction in iron burden, including a significant improvement in overall survival [4,12] . However, the effectiveness of chelation therapy is heavily reliant on good compliance. In one study, patients with -thalassaemia who received 225 300 infusions of DFO annually were found to have a 95% chance of survival to age 20 and a 90% chance to age 30. In contrast, those with a low number of annual DFO infusions (0 75) had survival rates of 20% to age 20 and 0% by age 30 [4] . Treatment with DFO is demanding and inconvenient, as the regimen requires regular subcutaneous infusions over 8 12 h, 5 7 days per week, which often results in poor

    patient compliance [8] , particularly in adolescents and children. The drawbacks of chelation therapy with DFO led to the search for effective oral iron chelators with a good tolerability profile.

    Deferiprone was the first oral chelator to be licensed and is approved in a number of countries outside the USA and Canada for the treatment of adult patients with -thalassaemia major for whom DFO therapy is contraindicated or inadequate [13] . However, the use of deferiprone is limited partly due to the occurrence of serious adverse events during treatment, such as neutropenia and, less frequently, agranulocytosis [9,10] . Deferiprone is most commonly used in combination with DFO for patients with a high iron burden and serious iron-mediated cardiac disease. Studies evaluating the administration of both drugs sequentially have observed agranulocytosis only rarely using this administration regimen [14-16] . Nevertheless, both the safety profile and patient compliance with combination therapy require further research.

    Despite the availability of these agents, some heavily transfused patients are unable to achieve successful iron chelation, most likely due to poor compliance with DFO monotherapy or DFO plus deferiprone combination therapy.

    3. Introduction to deferasirox

    Deferasirox was developed in response to the significant clinical need for a convenient, effective and well tolerated iron chelator. Approximately 700 compounds were synthesised and subjected to a rigorous filtering process, which included the determination of iron-binding potency, selectivity, oral activity, and subchronic tolerability in animals at a very early stage [17] . Of these compounds, deferasirox showed the most promising preclinical profile and was developed further.

    4. Chemistry

    Deferasirox is a novel, orally active tridentate ligand with a high affinity and specificity for iron [17] . The active molecule in deferasirox is a highly lipophilic, 99% protein-bound, N-substituted bis-hydroxyphenyl-triazole [17,18] . Three polar interaction sites in the binding pocket results in deferasirox binding with iron in a 2:1 ratio. That is, two deferasirox molecules are required to form a stable complex with each iron (Fe 3+ ) atom ( Figure 1 ).

    5. Pharmacokinetics and pharmacodynamics

    Preclinical studies in a range of animal models have demonstrated that single, oral doses of radio-labelled deferasirox are rapidly absorbed and maximal concentrations are reached 0.5 1 h postdose [17] . Deferasirox efficiently and selectively mobilises iron from liver and heart tissue, thereby promoting iron excretion [18,19] . In preclinical studie

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