Long-term experience with deferasirox (ICL670), a once-daily oral iron chelator, in the treatment of transfusional iron overload

Download Long-term experience with deferasirox (ICL670), a once-daily oral iron chelator, in the treatment of transfusional iron overload

Post on 02-Feb-2017

218 views

Category:

Documents

4 download

Embed Size (px)

TRANSCRIPT

<ul><li><p>Drug Evaluation</p><p> 10.1517/14656560802335333 2008 Informa UK Ltd ISSN 1465-6566 2391All rights reserved: reproduction in whole or in part not permitted</p><p> Long-term experience with deferasirox (ICL670), a once-daily oral iron chelator, in the treatment of transfusional iron overload MD Cappellini &amp; A Taher University of Milan, Department of Internal Medicine, Policlinico Foundation IRCCS, Milan, Italy </p><p> 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. </p><p> Keywords: deferasirox , effective , Exjade , transfusional iron overload </p><p> Expert Opin. Pharmacother. (2008) 9(13):2391-2402 </p><p> 1. Introduction </p><p> 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] . </p><p> 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 </p><p>1. Introduction</p><p>2. Overview of the market</p><p>3. Introduction to deferasirox</p><p>4. Chemistry</p><p>5. Pharmacokinetics and </p><p>pharmacodynamics</p><p>6. Clinical experience </p><p>with deferasirox</p><p>7. Safety and tolerability</p><p>8. Regulatory affairs</p><p>9. Conclusions</p><p>10. Expert opinion</p><p>11. Five-year view</p><p>Exp</p><p>ert O</p><p>pin.</p><p> Pha</p><p>rmac</p><p>othe</p><p>r. D</p><p>ownl</p><p>oade</p><p>d fr</p><p>om in</p><p>form</p><p>ahea</p><p>lthca</p><p>re.c</p><p>om b</p><p>y Q</p><p>ueen</p><p>'s U</p><p>nive</p><p>rsity</p><p> on </p><p>08/1</p><p>8/14</p><p>For </p><p>pers</p><p>onal</p><p> use</p><p> onl</p><p>y.</p></li><li><p>Deferasirox (ICL670)</p><p>2392 Expert Opin. Pharmacother. (2008) 9(13)</p><p>to the occurrence of serious adverse events during treatment, such as neutropenia and agranulocytosis [9,10] . </p><p> 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] . </p><p> 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. </p><p> 2. Overview of the market </p><p> 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 . </p><p> 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 </p><p>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. </p><p> 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. </p><p> 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. </p><p> 3. Introduction to deferasirox </p><p> 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. </p><p> 4. Chemistry </p><p> 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 ). </p><p> 5. Pharmacokinetics and pharmacodynamics </p><p> 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 studies, deferasirox was more effective than DFO in </p><p>Exp</p><p>ert O</p><p>pin.</p><p> Pha</p><p>rmac</p><p>othe</p><p>r. D</p><p>ownl</p><p>oade</p><p>d fr</p><p>om in</p><p>form</p><p>ahea</p><p>lthca</p><p>re.c</p><p>om b</p><p>y Q</p><p>ueen</p><p>'s U</p><p>nive</p><p>rsity</p><p> on </p><p>08/1</p><p>8/14</p><p>For </p><p>pers</p><p>onal</p><p> use</p><p> onl</p><p>y.</p></li><li><p>Cappellini &amp; Taher</p><p> Expert Opin. Pharmacother. (2008) 9(13) 2393</p><p> Table 1 . Characteristics of currently available iron chelators. </p><p> DFO Deferiprone Deferasirox </p><p>Dose range 20 60 mg/kg/day 50 100 mg/kg/day 20 30 mg/kg/day</p><p>Half-life 20 min 2 3 h 8 16 h</p><p>Administration Subcutaneous or intravenous Oral, three times daily Oral, once daily</p><p>Iron excretion Urine/stool Urine Stool</p><p>Guidelines for monitoring therapy</p><p>Quarterly: serum ferritin levels Weekly: CBC with differential Ongoing: blood transfusion rate</p><p>Quarterly: serum ferritin levels Monthly: serum ferritin, serum creatinine and ALT levels, proteinuria</p><p>Annually: auditory/eye exams, liver iron assessment, cardiac iron assessment in patients 10 years old</p><p>Annually: liver iron assessment, cardiac iron assessment in patients 10 years old</p><p>Annually: liver iron assessment, cardiac iron assessment in patients 10 years old, auditory and ophthalmic testing, paediatric growth</p><p>Other: ALT level monthly for 3 6 months, then every 6 months</p><p>Advantages Long-term experience Orally active Orally active</p><p>Effective in reducing body iron stores</p><p>Well established safety profi le</p><p>May reverse cardiac disease Enhanced removal of cardiac iron Once-daily administration</p><p>May be combined with deferiprone May be combined with DFO Equivalent effi cacy to DFO at doses 20 mg/kg/day</p><p>Disadvantages Requires continuous infusion May not achieve negative iron balance at 75 mg/kg/day</p><p>Need to monitor renal function</p><p>Poor compliance Risk of agranulocytosis Long-term data gathering is ongoing</p><p>Potential ear, eye, bone toxicity Need for weekly blood counts May not achieve negative iron balance at lower doses</p><p> Adapted from research originally published in Cohen [49] , Copyright (2006) The American Society of Hematology. ALT: Alanine aminotransferase; CBC: Complete blood count; DFO: Deferoxamine. </p><p>mobilising iron from the hepatocellular pool [17] and from cardiomyocytes [20,21] . Deferasirox is predominantly metabolised by glucoronidation, with subsequent biliary excretion [19] . Deferasirox and its metabolites are mainly excreted in the faeces (84% of the dose); renal excretion is minimal (8% of the dose, 6% as hydroxylated deferasirox). Importantly, deferasirox does not promote uptake of dietary iron, which was considered a potential complication during the search for oral iron chelators [17] . </p><p> Early studies demonstrated that the oral bioavailability of deferasirox is 70% and serum concentration is proportional to the dose administered [22,23] . As deferasirox has a mean elimination half-life of 8 16 h, plasma levels are maintained within the therapeutic range over a 24 h period. Deferasirox can therefore provide 24 h chelation coverage with once-daily administration ( Figure 2 ) [23,24] , thus providing sustained protection from toxic labile iron [25] . The efficiency of deferasirox in terms of iron-binding capacity is estimated to be approximately 27% [26] . </p><p> 6. Clinical experience with deferasirox </p><p> The deferasirox clinical development programme is the largest ever conducted for any chelation therapy and has to date enrolled more than 1000 patients. Five pivotal clinical studies have assessed the efficacy, safety and tolerability of deferasirox across a number of transfusion-dependent anaemias. Around half of all enrolled patients were children, some as young as 2 years old. Older patients were also well represented in the -thalassaemia and MDS populations. To date, some patients in the deferasirox clinical programme have been receiving treatment for up to 4 years. </p><p> A randomised, double-blind, placebo-controlled, dose-escalation study in 24 iron-overloaded patients with -thalassaemia first demonstrated that deferasirox could reduce iron burden in humans [23] . Pharmacokinetic evaluations in this study were consistent with preclinical evidence that deferasirox is absorbed promptly and is detectable in the blood for 24 h. The plasma concentration of deferasirox was </p><p>Exp</p><p>ert O</p><p>pin.</p><p> Pha</p><p>rmac</p><p>othe</p><p>r. D</p><p>ownl</p><p>oade</p><p>d fr</p><p>om in</p><p>form</p><p>ahea</p><p>lthca</p><p>re.c</p><p>om b</p><p>y Q</p><p>ueen</p><p>'s U</p><p>nive</p><p>rsity</p><p> on </p><p>08/1</p><p>8/14</p><p>For </p><p>pers</p><p>onal</p><p> use</p><p> onl</p><p>y.</p></li><li><p>Deferasirox (ICL670)</p><p>2394 Expert Opin. Pharmacother. (2008) 9(13)</p><p>also found to be proportional to dose. Although three dose groups (10, 20 or 40 mg/kg/day) were evaluated and all three doses resulted in a positive net iron excretion, the investigators concluded that deferasirox 20 30 mg/kg/day offered the most effective chelation combined with reasonable tolerability. Based on these findings, the recommended starting dose of deferasirox for most patients is 20 mg/kg/day, although this should be modified depending on the number of transfusions a patient is receiving and whether the patients therapeutic goal is to decrease or maintain body iron levels. </p><p> Another open-label, noncomparative, 48-week trial of deferasirox 10 mg/kg/day assessed the safety, tolerability, long-term pharmacokinetics and efficacy [via changes in liver iron concentration (LIC) and serum ferritin] in 40 paediatric patients (2 17 years old) with -thalassaemia and transfusional overload ( Table 2 ) [27] . After 48 weeks, the mean deferasirox dose was 11.3 mg/kg/day. Results showed that overa...</p></li></ul>

Recommended

View more >