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Maria Domenica Cappellini - One of the best experts on this subject based on the ideXlab platform.
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one year results from a prospective randomized trial comparing phlebotomy with Deferasirox for the treatment of iron overload in pediatric patients with thalassemia major following curative stem cell transplantation
Pediatric Blood & Cancer, 2017Co-Authors: Adlette Inati, Mario Kahale, Nada Sbeiti, Suzanne Koussa, Therese Abi Nasr, Khaled M. Musallam, Ali T. Taher, Maria Domenica Cappellini, Hussein A. AbbasAbstract:Background Iron overload is well documented in patients with β-thalassemia major, and patients who have undergone hematopoietic stem cell transplantation (HSCT) remain at risk as a result of pre- and immediate post-HSCT transfusions. Procedure This is a prospective, randomized, 1-year clinical trial that compares the efficacy and safety of the once-daily oral iron chelator Deferasirox versus phlebotomy for the treatment of iron overload in children with β-thalassemia major following HSCT. Results Patients (aged 12.4 years) received Deferasirox (n = 12, 10 mg/kg/day starting dose) or phlebotomy (n = 14, 6 ml/kg/2 weeks) for 1 year. In two and five patients, Deferasirox dose was increased to 15 and 20 mg/kg/day, respectively. Magnetic resonance imaging (MRI)–assessed liver iron concentration (LIC) decreased with Deferasirox (mean 12.5 ± 10.1 to 8.5 ± 9.3 mg Fe/g dry weight [dw]; P = 0.0005 vs. baseline) and phlebotomy (10.2 ± 6.8 to 8.3 ± 9.2 mg Fe/g dw; P = 0.05). LIC reductions were greater with Deferasirox than with phlebotomy for patients with baseline serum ferritin 1,000 ng/ml or higher (–8.1 ± 1.5 vs. –3.5 ± 5.7 mg Fe/g dw; P = 0.048). Serum ferritin and non-transferrin-bound iron also decreased significantly. In two patients with severe cardiac siderosis, a clinically relevant improvement in myocardial T2* was seen, following phlebotomy and Deferasirox therapy (n = 1 each). Adverse effects with Deferasirox were skin rash, gastrointestinal upset, and increased liver function tests (all n = 1), while those for phlebotomy were difficulty with venous access (n = 4) and distress during procedure (n = 1). Parents of 13/14 children receiving phlebotomy wished to switch to Deferasirox, with 1/14 being satisfied with phlebotomy. Conclusions Deferasirox treatment or phlebotomy reduces iron burden in pediatric patients with β- thalassemia major post-HSCT, with a manageable safety profile.
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Efficacy and Safety of Deferasirox
Oncology & Hematology Review (US), 2009Co-Authors: Maria Domenica Cappellini, Laura ZanaboniAbstract:Deferasirox represents a new class of once-daily iron chelators. It was first licensed in 2005 for the treatment of adult and pediatric patients with chronic iron overload due to blood transfusions. These approvals were based on data from the core program of one-year clinical trials, which involved more than 1,000 patients in what is the largest and most rigorous prospective clinical evaluation of any iron-chelating agent to date. Deferasirox has been studied in adults and children with a wide range of conditions, including β-thalassemia, myelodysplastic syndromes, and sickle cell disease. Recent data have highlighted the importance of timely Deferasirox dose adjustments and described the efficacy and safety of Deferasirox at doses >30mg/kg/day. The pharmacokinetic profile of Deferasirox across all age groups shows it to be well absorbed, with a mean elimination half-life of eight to 16 hours that supports once-daily dosing. In clinical trials, Deferasirox has demonstrated consistent dose-dependent efficacy, producing sustained reductions in serum ferritin, labile plasma iron, and cardiac iron load. The safety profile of Deferasirox presents mostly as mild adverse events (primarily gastrointestinal symptoms, skin rash, and increases in serum creatinine) that resolve rapidly with no reports of progressive renal, hepatic, or bone marrow effects. This adverse event profile is seen to be manageable with appropriate clinical monitoring. Data from the extension phases of these studies are beginning to accumulate, with experience of up to seven years of Deferasirox therapy now available. Deferasirox represents a significant development in the treatment of iron overload and has further potential applications.
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Effect of food, type of food, and time of food intake on Deferasirox bioavailability: recommendations for an optimal Deferasirox administration regimen
Journal of clinical pharmacology, 2008Co-Authors: Renzo Galanello, Maria Domenica Cappellini, Antonio Piga, Rossella Belleli, Gian Luca Forni, Antonella Zappu, Raffaella Origa, Catherine Dutreix, John Ford, Gilles J. RiviereAbstract:Deferasirox (ICL670) is representative of a new class of tridentate iron chelators, formulated as tablets for dispersion. Deferasirox has exhibited high potency and a clinically manageable safety profile in preclinical models and in an extensive clinical program. The effect of food and time of food intake on the pharmacokinetics of Deferasirox was investigated in healthy volunteers and patients with transfusional hemosiderosis. The bioequivalence of a single oral dose of Deferasirox (20 mg/kg) was assessed following administration either before a high-fat or standard breakfast or concurrent with a standard breakfast in comparison with fasted conditions in healthy volunteers. The bioavailability of Deferasirox was determined following a single oral dose (20 mg/kg) under fed and fasted conditions in patients. These data show that the type of food, caloric content, and fat content of the meal influence the bioavailability of Deferasirox when consumed concomitantly. In contrast, this is not the case when Deferasirox is administered at least 30 minutes before a meal. In conclusion, it is recommended that Deferasirox be administered at least 30 minutes prior to meals. When this is not feasible, Deferasirox should be administered consistently at the same time before meals to limit the sources of variability that affect absorption.
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Long-term efficacy and safety of Deferasirox.
Blood Reviews, 2008Co-Authors: Maria Domenica CappelliniAbstract:Summary Deferasirox is an oral iron chelator, with a long half-life, that can be given once daily, because it provides a 24-hour chelation. Several phase II trials and a pivotal phase III trial have established that, in transfusion-dependent patients with β-thalassaemia major, Deferasirox has a similar efficacy to previously available deferoxamine. A Deferasirox dose of 20 mg/kg/day stabilizes serum ferritin levels and liver iron concentration, while a dose of 30 mg/kg/day reduces serum ferritin and liver iron concentration and achieves negative iron balance. Efficacy has also been shown across various transfusion-dependent anaemias including myelodysplastic syndromes, sickle cell disease, and other rare transfusion-dependent anaemias. Deferasirox is generally well tolerated, with the most common adverse events being gastrointestinal disturbances and rash. Longer-term studies with a median follow-up of 3.5 years have confirmed the efficacy and safety of Deferasirox. It is recommended that patients treated with Deferasirox are monitored regularly for iron status and adverse events, to ensure that an effective and tolerable iron chelation regimen is established for each individual patient.
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Long-term efficacy and safety of Deferasirox.
Blood reviews, 2008Co-Authors: Maria Domenica CappelliniAbstract:Deferasirox is an oral iron chelator, with a long half-life, that can be given once daily, because it provides a 24-hour chelation. Several phase II trials and a pivotal phase III trial have established that, in transfusion-dependent patients with beta-thalassaemia major, Deferasirox has a similar efficacy to previously available deferoxamine. A Deferasirox dose of 20 mg/kg/day stabilizes serum ferritin levels and liver iron concentration, while a dose of 30 mg/kg/day reduces serum ferritin and liver iron concentration and achieves negative iron balance. Efficacy has also been shown across various transfusion-dependent anaemias including myelodysplastic syndromes, sickle cell disease, and other rare transfusion-dependent anaemias. Deferasirox is generally well tolerated, with the most common adverse events being gastrointestinal disturbances and rash. Longer-term studies with a median follow-up of 3.5 years have confirmed the efficacy and safety of Deferasirox. It is recommended that patients treated with Deferasirox are monitored regularly for iron status and adverse events, to ensure that an effective and tolerable iron chelation regimen is established for each individual patient.
Ali T. Taher - One of the best experts on this subject based on the ideXlab platform.
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one year results from a prospective randomized trial comparing phlebotomy with Deferasirox for the treatment of iron overload in pediatric patients with thalassemia major following curative stem cell transplantation
Pediatric Blood & Cancer, 2017Co-Authors: Adlette Inati, Mario Kahale, Nada Sbeiti, Suzanne Koussa, Therese Abi Nasr, Khaled M. Musallam, Ali T. Taher, Maria Domenica Cappellini, Hussein A. AbbasAbstract:Background Iron overload is well documented in patients with β-thalassemia major, and patients who have undergone hematopoietic stem cell transplantation (HSCT) remain at risk as a result of pre- and immediate post-HSCT transfusions. Procedure This is a prospective, randomized, 1-year clinical trial that compares the efficacy and safety of the once-daily oral iron chelator Deferasirox versus phlebotomy for the treatment of iron overload in children with β-thalassemia major following HSCT. Results Patients (aged 12.4 years) received Deferasirox (n = 12, 10 mg/kg/day starting dose) or phlebotomy (n = 14, 6 ml/kg/2 weeks) for 1 year. In two and five patients, Deferasirox dose was increased to 15 and 20 mg/kg/day, respectively. Magnetic resonance imaging (MRI)–assessed liver iron concentration (LIC) decreased with Deferasirox (mean 12.5 ± 10.1 to 8.5 ± 9.3 mg Fe/g dry weight [dw]; P = 0.0005 vs. baseline) and phlebotomy (10.2 ± 6.8 to 8.3 ± 9.2 mg Fe/g dw; P = 0.05). LIC reductions were greater with Deferasirox than with phlebotomy for patients with baseline serum ferritin 1,000 ng/ml or higher (–8.1 ± 1.5 vs. –3.5 ± 5.7 mg Fe/g dw; P = 0.048). Serum ferritin and non-transferrin-bound iron also decreased significantly. In two patients with severe cardiac siderosis, a clinically relevant improvement in myocardial T2* was seen, following phlebotomy and Deferasirox therapy (n = 1 each). Adverse effects with Deferasirox were skin rash, gastrointestinal upset, and increased liver function tests (all n = 1), while those for phlebotomy were difficulty with venous access (n = 4) and distress during procedure (n = 1). Parents of 13/14 children receiving phlebotomy wished to switch to Deferasirox, with 1/14 being satisfied with phlebotomy. Conclusions Deferasirox treatment or phlebotomy reduces iron burden in pediatric patients with β- thalassemia major post-HSCT, with a manageable safety profile.
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Efficacy of Deferasirox in transfusion dependent and non-transfusion-dependent thalassemias
Journal of symptoms and signs, 2014Co-Authors: Ali T. Taher, Nour MoukalledAbstract:Background Chronic iron overload is an inevitable complication affecting patients with thalassemia either as a result of regular blood transfusions (transfusion dependent patients), or due to increased gastrointestinal iron absorption as a consequence of ineffective erythropoiesis and chronic hypoxia (non-transfusion-dependent thalassemia). Appropriate iron chelation has been shown to improve patients’ outcomes, and prevent the morbidity and mortality associated with this serious complication. Deferasirox, a once-daily oral iron chelator, has been approved for the treatment of transfusional iron overload in adult and pediatric patients. Furthermore, Deferasirox is the only chelator approved for use in non-transfusion-dependent thalassemia. Areas Covered In addition to the pharmacokinetic properties of Deferasirox, this review presents short and long-term efficacy and safety data from pivotal clinical trials evaluating Deferasirox in iron-overloaded patients with transfusion dependent and non-transfusion- dependent thalassemias. Results/Conclusion According to the available data, Deferasirox is a convenient and effective iron chelator with a clinically manageable safety profile. However, some patients are still not adequately chelated, and further research is still needed to provide the best management for this highly variable population of patients. Keywords: Deferasirox; iron overload; iron chelation; transfusion dependent thalassemia; non-transfusion-dependent thalassemias. Received: June 30, 2013; Accepted: October 1, 2013; Published: January 10, 2014 Corresponding Author: Ali Taher, Department of Internal Medicine, Hematology-Oncology Division, American University of Beirut Medical Center, Riad El Solh 1107 2020, Beirut, Lebanon. E-mail: ataher@aub.edu.lb .
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Deferasirox effectively reduces iron overload in non transfusion dependent thalassemia ntdt patients 1 year extension results from the thalassa study
Annals of Hematology, 2013Co-Authors: Ali T. Taher, John B. Porter, Antonis Kattamis, Renzo Galanello, Vip Viprakasit, Suporn Chuncharunee, Pranee Sutcharitchan, Noppadol Siritanaratkul, Zeynep Karakas, Tomasz LawniczekAbstract:Patients with non-transfusion-dependent thalassemia (NTDT) often develop iron overload that requires chelation to levels below the threshold associated with complications. This can take several years in patients with high iron burden, highlighting the value of long-term chelation data. Here, we report the 1-year extension of the THALASSA trial assessing Deferasirox in NTDT; patients continued with Deferasirox or crossed from placebo to Deferasirox. Of 133 patients entering extension, 130 completed. Liver iron concentration (LIC) continued to decrease with Deferasirox over 2 years; mean change was −7.14 mg Fe/g dry weight (dw) (mean dose 9.8 ± 3.6 mg/kg/day). In patients originally randomized to placebo, whose LIC had increased by the end of the core study, LIC decreased in the extension with Deferasirox with a mean change of −6.66 mg Fe/g dw (baseline to month 24; mean dose in extension 13.7 ± 4.6 mg/kg/day). Of 166 patients enrolled, 64 (38.6 %) and 24 (14.5 %) patients achieved LIC <5 and <3 mg Fe/g dw by the end of the study, respectively. Mean LIC reduction was greatest in patients with the highest pretreatment LIC. Deferasirox progressively decreases iron overload over 2 years in NTDT patients with both low and high LIC. Safety profile of Deferasirox over 2 years was consistent with that in the core study.
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reduction in labile plasma iron during treatment with Deferasirox a once daily oral iron chelator in heavily iron overloaded patients with β thalassaemia
European Journal of Haematology, 2009Co-Authors: Shahina Daar, Hanspeter Nick, Anil Pathare, Ulrike Kriemlerkrahn, Abdel Hmissi, Dany Habr, Ali T. TaherAbstract:This subgroup analysis evaluated the effect of once-daily oral Deferasirox on labile plasma iron (LPI) levels in patients from the prospective, 1-yr, multicentre ESCALATOR study. Mean baseline liver iron concentration and median serum ferritin levels were 28.6 ± 10.3 mg Fe/g dry weight and 6334 ng/mL respectively, indicating high iron burden despite prior chelation therapy. Baseline LPI levels (0.98 ± 0.82 μmol/L) decreased significantly to 0.12 ± 0.16 μmol/L, 2 h after first Deferasirox dose (P=0.0006). Reductions from pre- to post-Deferasirox administration were also observed at all other time points. Compared to baseline, there was a significant reduction in preadministration LPI that reached the normal range at week 4 and throughout the remainder of the study (P≤0.02). Pharmacokinetic analysis demonstrated an inverse relationship between preadministration LPI levels and trough Deferasirox plasma concentrations. Once-daily dosing with Deferasirox ≥20 mg/kg/d provided sustained reduction in LPI levels in these heavily iron-overloaded patients, suggesting 24-h protection from LPI. Deferasirox may therefore reduce unregulated tissue iron loading and prevent further end-organ damage.
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long term experience with Deferasirox icl670 a once daily oral iron chelator in the treatment of transfusional iron overload
Expert Opinion on Pharmacotherapy, 2008Co-Authors: Ali T. TaherAbstract: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.
Renzo Galanello - One of the best experts on this subject based on the ideXlab platform.
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Deferasirox effectively reduces iron overload in non transfusion dependent thalassemia ntdt patients 1 year extension results from the thalassa study
Annals of Hematology, 2013Co-Authors: Ali T. Taher, John B. Porter, Antonis Kattamis, Renzo Galanello, Vip Viprakasit, Suporn Chuncharunee, Pranee Sutcharitchan, Noppadol Siritanaratkul, Zeynep Karakas, Tomasz LawniczekAbstract:Patients with non-transfusion-dependent thalassemia (NTDT) often develop iron overload that requires chelation to levels below the threshold associated with complications. This can take several years in patients with high iron burden, highlighting the value of long-term chelation data. Here, we report the 1-year extension of the THALASSA trial assessing Deferasirox in NTDT; patients continued with Deferasirox or crossed from placebo to Deferasirox. Of 133 patients entering extension, 130 completed. Liver iron concentration (LIC) continued to decrease with Deferasirox over 2 years; mean change was −7.14 mg Fe/g dry weight (dw) (mean dose 9.8 ± 3.6 mg/kg/day). In patients originally randomized to placebo, whose LIC had increased by the end of the core study, LIC decreased in the extension with Deferasirox with a mean change of −6.66 mg Fe/g dw (baseline to month 24; mean dose in extension 13.7 ± 4.6 mg/kg/day). Of 166 patients enrolled, 64 (38.6 %) and 24 (14.5 %) patients achieved LIC <5 and <3 mg Fe/g dw by the end of the study, respectively. Mean LIC reduction was greatest in patients with the highest pretreatment LIC. Deferasirox progressively decreases iron overload over 2 years in NTDT patients with both low and high LIC. Safety profile of Deferasirox over 2 years was consistent with that in the core study.
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Deferasirox: pharmacokinetics and clinical experience.
Expert opinion on drug metabolism & toxicology, 2011Co-Authors: Renzo Galanello, Simona Campus, Raffaella OrigaAbstract:Introduction: Iron overload is an inevitable consequence of transfusion therapy for a variety of underlying anemias. Iron overload, without effective chelation, will lead to significant morbidity and mortality. Deferasirox (Exjade®) is an oral tridentate iron chelator used for reducing iron overload. Areas covered: In addition to the pharmacokinetic and pharmacodynamic profile of Deferasirox, this review examines the efficacy and safety data from pivotal studies with Deferasirox in iron-overloaded patients with various anemias, including thalassemia, sickle cell disease and myelodysplastic syndromes. A qualitative literature search for Deferasirox was performed using PubMed and recent key congress publications (EHA and ASH); key search terms were Deferasirox, pharmacokinetic, pharmacodynamic, efficacy and safety. Expert opinion: Based on the current available data, Deferasirox treatment is effective with a clinically manageable safety profile although appropriate dosing according to the severity of iron b...
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Effect of food, type of food, and time of food intake on Deferasirox bioavailability: recommendations for an optimal Deferasirox administration regimen
Journal of clinical pharmacology, 2008Co-Authors: Renzo Galanello, Maria Domenica Cappellini, Antonio Piga, Rossella Belleli, Gian Luca Forni, Antonella Zappu, Raffaella Origa, Catherine Dutreix, John Ford, Gilles J. RiviereAbstract:Deferasirox (ICL670) is representative of a new class of tridentate iron chelators, formulated as tablets for dispersion. Deferasirox has exhibited high potency and a clinically manageable safety profile in preclinical models and in an extensive clinical program. The effect of food and time of food intake on the pharmacokinetics of Deferasirox was investigated in healthy volunteers and patients with transfusional hemosiderosis. The bioequivalence of a single oral dose of Deferasirox (20 mg/kg) was assessed following administration either before a high-fat or standard breakfast or concurrent with a standard breakfast in comparison with fasted conditions in healthy volunteers. The bioavailability of Deferasirox was determined following a single oral dose (20 mg/kg) under fed and fasted conditions in patients. These data show that the type of food, caloric content, and fat content of the meal influence the bioavailability of Deferasirox when consumed concomitantly. In contrast, this is not the case when Deferasirox is administered at least 30 minutes before a meal. In conclusion, it is recommended that Deferasirox be administered at least 30 minutes prior to meals. When this is not feasible, Deferasirox should be administered consistently at the same time before meals to limit the sources of variability that affect absorption.
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Once-daily oral Deferasirox for the treatment of transfusional iron overload.
Expert review of clinical pharmacology, 2008Co-Authors: Renzo Galanello, Raffaella OrigaAbstract:The increasing use of blood transfusions, combined with extended patient survival, has led to an increase in the number of patients at risk of developing transfusional iron overload. Clinical data have shown that the once-daily oral iron chelator Deferasirox is effective in adults and children with various transfusion-dependent anemias, including β-thalassemia and the myelodysplastic syndromes. Deferasirox has a defined, clinically manageable safety profile. The most common treatment-related adverse events are mild gastrointestinal disorders, skin rash and mild, nonprogressive serum creatinine increases. The Deferasirox clinical trial program is continuing in Phase II/III extension phases and Phase IV trials. Long-term data continue to support the efficacy and safety of Deferasirox. Convenient, effective and tolerable chelation therapy with Deferasirox is a significant development in the treatment of transfusional iron overload.
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randomized phase ii trial of Deferasirox exjade icl670 a once daily orally administered iron chelator in comparison to deferoxamine in thalassemia patients with transfusional iron overload
Haematologica, 2006Co-Authors: Antonio Piga, Maria Domenica Cappellini, Renzo Galanello, Gian Luca Forni, Raffaella Origa, Antonietta Zappu, Guido Donato, Elena Bordone, Antonella Lavagetto, Laura ZanaboniAbstract:BACKGROUND AND OBJECTIVES: Iron accumulation is an inevitable consequence of chronic blood transfusions and results in serious complications in the absence of chelation treatment to remove excess iron. Deferoxamine (Desferal, DFO) reduces morbidity and mortality although the administration schedule of slow, parenteral infusions several days each week limits compliance and negatively affects long-term outcome. Deferasirox (Exjade, ICL670) is an oral chelator with high iron-binding potency and selectivity. In a phase II study, the tolerability and efficacy of Deferasirox were compared with those of DFO in 71 adults with transfusional hemosiderosis. DESIGN AND METHODS: Patients were randomized to receive once-daily Deferasirox (10 or 20 mg/kg; n=24 in both groups) or DFO (40 mg/kg, 5 days/week; n=23) for 48 weeks. Results. Both treatments were well tolerated and no patient discontinued Deferasirox due to drug-related adverse events. The reported frequency of transient, mild to moderate gastrointestinal disturbances was higher in the Deferasirox group than in the DFO group, but these disturbances settled spontaneously without dose interruption in all patients. Decreases in liver iron concentration (LIC) were comparable in the Deferasirox 20 mg/kg/day and DFO groups; baseline values of 8.5 and 7.9 mg Fe/g dw fell to 6.6 and 5.9 mg Fe/g dw, respectively, by week 48. Deferasirox showed a plasma elimination half-life of 8-16 hours, supporting its once-daily administration. INTERPRETATION AND CONCLUSIONS: Deferasirox at daily doses of 10 or 20 mg/kg was well tolerated and, at 20 mg/kg, showed similar efficacy to DFO 40 mg/kg in terms of decreases in LIC.
Hagit Miskin - One of the best experts on this subject based on the ideXlab platform.
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Deferasirox treatment may be associated with reversible renal fanconi syndrome
American Journal of Hematology, 2009Co-Authors: Ehud Evenor, Rachel Beckercohen, Hagit MiskinAbstract:Two cases of reversible renal Fanconi syndrome associated with Deferasirox treatment are reported. One of these recurred upon rechallenge. Deferasirox (Exjade") is a new once daily oral iron chelator for the treatment of chronic iron overload due to blood transfusions. Deferasirox became available in the USA in 2005 and is licensed in over 70 countries worldwide [1]. Preclinical studies in animals indicated that the kidney was a potential target organ of toxicity [2]. However, in phase II and III clinical trials, Deferasirox was found to be generally well tolerated [3-5]. Cases of fatal, acute, irreversible renal failure have been described in a post marketing report on Deferasirox [6], but details of the incidence rate or cause of these adverse events have not yet been reported, raising concerns regarding the toxicity of the drug. Renal Fanconi syndrome is a rare disorder in which the proximal tubular function of the kidney is impaired, resulting in decreased reabsorption of electrolytes and nutrients into the bloodstream. The solutes involved include glucose, amino acids, uric acid, phosphate, and bicarbonate. Both patients described below, having transfusion related iron overload, developed renal tubular dysfunction.
John B. Porter - One of the best experts on this subject based on the ideXlab platform.
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sustained improvements in myocardial t2 over 2 years in severely iron overloaded patients with beta thalassemia major treated with Deferasirox or deferoxamine
American Journal of Hematology, 2015Co-Authors: Dudley J Pennell, Antonio Piga, John B. Porter, Yurdanur Kilinc, Yongrong Lai, Amal Elbeshlawy, Mohsen Saleh Elalfy, Akif Yesilipek, Dany Habr, Khaled M. MusallamAbstract:Long-term controlled studies are needed to inform on the clinical benefit of chelation therapy for myocardial iron removal in transfusion-dependent beta thalassemia patients. In a 1-year nonrandomized extension to the CORDELIA study, data collected from patients with myocardial siderosis provided additional information on Deferasirox or deferoxamine (DFO) efficacy and safety. Myocardial (m)T2* increased from baseline 11.6 to 15.9 ms in patients receiving Deferasirox for 24 months (n = 74; geometric mean [Gmean ] ratio of month 24/baseline 1.38 [95% confidence interval 1.28, 1.49]) and from 10.8 to 14.2 ms in those receiving DFO (n = 29; Gmean ratio 1.33 [1.13, 1.55]; P = 0.93 between groups). Improved mT2* with Deferasirox was evident across all subgroups evaluated irrespective of baseline myocardial (mT2* < 10 vs. ≥ 10 ms) or liver (LIC <15 vs. ≥15 mg Fe/g dw) iron burden. Mean LVEF was stable and remained within normal limits with Deferasirox or DFO. Liver iron concentration decreased from high baseline values of 30.6 ± 18.0 to 14.4 ± 16.6 mg Fe/g dw at month 24 in Deferasirox patients and from 36.8 ± 15.6 to 11.0 ± 12.1 mg Fe/g dw in DFO patients. The long-term safety profile of Deferasirox or DFO was consistent with previous reports; serious drug-related AEs were reported in 6.8% of Deferasirox and 6.9% of DFO patients. Continued treatment of severely iron-overloaded beta thalassemia patients with Deferasirox or DFO led to sustained improvements in myocardial iron irrespective of high or low baseline myocardial or liver iron burden, in parallel with substantial improvements in liver iron (Clinicaltrials.gov identifier: NCT00600938).
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a 1 year randomized controlled trial of Deferasirox vs deferoxamine for myocardial iron removal in β thalassemia major cordelia
Blood, 2014Co-Authors: Dudley J Pennell, Antonio Piga, John B. Porter, Yurdanur Kilinc, Yongrong Lai, Amal Elbeshlawy, Khawla Belhoul, Mohsen Saleh Elalfy, Akif Yesilipek, Tomasz LawniczekAbstract:Randomized comparison data on the efficacy and safety of Deferasirox for myocardial iron removal in transfusion dependent patients are lacking. CORDELIA was a prospective, randomized comparison of Deferasirox (target dose 40 mg/kg per day) vs subcutaneous deferoxamine (50-60 mg/kg per day for 5-7 days/week) for myocardial iron removal in 197 β-thalassemia major patients with myocardial siderosis (T2* 6-20 milliseconds) and no signs of cardiac dysfunction (mean age, 19.8 years). Primary objective was to demonstrate noninferiority of Deferasirox for myocardial iron removal, assessed by changes in myocardial T2* after 1 year using a per-protocol analysis. Geometric mean (Gmean) myocardial T2* improved with Deferasirox from 11.2 milliseconds at baseline to 12.6 milliseconds at 1 year (Gmeans ratio, 1.12) and with deferoxamine (11.6 milliseconds to 12.3 milliseconds; Gmeans ratio, 1.07). The between-arm Gmeans ratio was 1.056 (95% confidence interval [CI], 0.998, 1.133). The lower 95% CI boundary was greater than the prespecified margin of 0.9, establishing noninferiority of Deferasirox vs deferoxamine (P = .057 for superiority of Deferasirox). Left ventricular ejection fraction remained stable in both arms. Frequency of drug-related adverse events was comparable between Deferasirox (35.4%) and deferoxamine (30.8%). CORDELIA demonstrated the noninferiority of Deferasirox compared with deferoxamine for myocardial iron removal. This trial is registered at www.clinicaltrials.gov as #NCT00600938.
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Deferasirox effectively reduces iron overload in non transfusion dependent thalassemia ntdt patients 1 year extension results from the thalassa study
Annals of Hematology, 2013Co-Authors: Ali T. Taher, John B. Porter, Antonis Kattamis, Renzo Galanello, Vip Viprakasit, Suporn Chuncharunee, Pranee Sutcharitchan, Noppadol Siritanaratkul, Zeynep Karakas, Tomasz LawniczekAbstract:Patients with non-transfusion-dependent thalassemia (NTDT) often develop iron overload that requires chelation to levels below the threshold associated with complications. This can take several years in patients with high iron burden, highlighting the value of long-term chelation data. Here, we report the 1-year extension of the THALASSA trial assessing Deferasirox in NTDT; patients continued with Deferasirox or crossed from placebo to Deferasirox. Of 133 patients entering extension, 130 completed. Liver iron concentration (LIC) continued to decrease with Deferasirox over 2 years; mean change was −7.14 mg Fe/g dry weight (dw) (mean dose 9.8 ± 3.6 mg/kg/day). In patients originally randomized to placebo, whose LIC had increased by the end of the core study, LIC decreased in the extension with Deferasirox with a mean change of −6.66 mg Fe/g dw (baseline to month 24; mean dose in extension 13.7 ± 4.6 mg/kg/day). Of 166 patients enrolled, 64 (38.6 %) and 24 (14.5 %) patients achieved LIC <5 and <3 mg Fe/g dw by the end of the study, respectively. Mean LIC reduction was greatest in patients with the highest pretreatment LIC. Deferasirox progressively decreases iron overload over 2 years in NTDT patients with both low and high LIC. Safety profile of Deferasirox over 2 years was consistent with that in the core study.
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Iron Chelation Adherence to Deferoxamine and Deferasirox in Thalassemia
American journal of hematology, 2011Co-Authors: Felicia Trachtenberg, John B. Porter, Elliott Vichinsky, Dru Haines, Zahra Pakbaz, Lauren Mednick, Amy Sobota, Janet L. Kwiatkowski, Alexis A. Thompson, Thomas D. CoatesAbstract:The Thalassemia Clinical Research Network collected adherence information from 79 patients on deferoxamine and 186 on Deferasirox from 2007 to 2009. Chelation adherence was defined as percent of doses administered in the last 4 weeks (patient report) out of those prescribed (chart review). Chelation history since 2002 was available for 97 patients currently on deferoxamine and 217 on Deferasirox, with crude estimates of adherence from chart review. Self-reported adherence to both deferoxamine and Deferasirox were quite high, with slightly higher adherence to the oral chelator (97 vs. 92%). Ninety percent of patients on Deferasirox reported at least 90% adherence, compared with 75% of patients on deferoxamine. Adherence to both chelators was highest in children, followed by adolescents and older adults. Predictors of lower deferoxamine adherence were smoking in the past year, problems sticking themselves (adults only), problems wearing their pump, and fewer transfusions in the past year. Predictors of lower Deferasirox adherence were bodily pain and depression. Switching chelators resulted in increased adherence, regardless of the direction of the switch, although switching from deferoxamine to Deferasirox was far more common. As adherence to deferoxamine is higher than previously reported, it appears beneficial for patients to have a choice in chelators.
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pharmacokinetics metabolism and disposition of Deferasirox in beta thalassemic patients with transfusion dependent iron overload who are at pharmacokinetic steady state
Drug Metabolism and Disposition, 2010Co-Authors: Felix Waldmeier, Gerard J M Bruin, Ulrike Glaenzel, Katharine Hazell, Romain Sechaud, Steve Warrington, John B. PorterAbstract:Deferasirox (ICL670) is a novel once-daily, orally administered iron chelator to treat chronic iron overload in patients with transfusion-dependent anemias. Absorption, distribution, metabolism, and excretion of [14C]Deferasirox at pharmacokinetic steady state was investigated in five adult beta-thalassemic patients. Deferasirox (1000 mg) was given orally once daily for 6 days to achieve steady state. On day 7, patients received a single oral 1000-mg dose (approximately 20 mg/kg) of [14C]Deferasirox (2.5 MBq). Blood, plasma, feces, and urine samples collected over 7 days were analyzed for radioactivity, Deferasirox, its iron complex Fe-[Deferasirox]2, and metabolites. Deferasirox was well absorbed. Deferasirox and its iron complex accounted for 87 and 10%, respectively, of the radioactivity in plasma (area under the curve at steady state). Excretion occurred largely in the feces (84% of dose), and 60% of the radioactivity in the feces was identified as Deferasirox. Apparently unchanged Deferasirox in feces was partly attributable to incomplete intestinal absorption and partly to hepatobiliary elimination of Deferasirox (including first-pass elimination) and of its glucuronide. Renal excretion was only 8% of the dose and included mainly the glucuronide M6. Oxidative metabolism by cytochrome 450 enzymes to M1 [5-hydroxy (OH) Deferasirox, presumably by CYP1A] and M4 (5'-OH Deferasirox, by CYP2D6) was minor (6 and 2% of the dose, respectively). Direct and indirect evidence indicates that the main pathway of Deferasirox metabolism is via glucuronidation to metabolites M3 (acyl glucuronide) and M6 (2-O-glucuronide).
