Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0039730 (thalassemia)
 10,305 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Deferasirox (ICL670) is a once-daily oral iron chelator developed for the treatment of chronic iron overload from blood transfusions. A comparative phase 3 trial was conducted to demonstrate the efficacy of deferasirox in regularly transfused patients with beta-thalassemia aged 2 years or older. Patients were randomized and received treatment with deferasirox (n = 296) or deferoxamine (n = 290), with dosing of each according to baseline liver iron concentration (LIC). The primary endpoint was maintenance or reduction of LIC; secondary endpoints included safety and tolerability, change in serum ferritin level, and net body iron balance. In both arms, patients with LIC values of 7 mg Fe/g dry weight (dw) or higher had significant and similar dose-dependent reductions in LIC and serum ferritin, and effects on net body iron balance. However, the primary endpoint was not met in the overall population, possibly due to the fact that proportionally lower doses of deferasirox relative to deferoxamine were administered to patients with LIC values less than 7 mg Fe/g dw. The most common adverse events included rash, gastrointestinal disturbances, and mild nonprogressive increases in serum creatinine. No agranulocytosis, arthropathy, or growth failure was associated with deferasirox administration. Deferasirox is a promising once-daily oral therapy for the treatment of transfusional iron overload.
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PMID:A phase 3 study of deferasirox (ICL670), a once-daily oral iron chelator, in patients with beta-thalassemia. 1692 97

Iron chelation therapy using deferoxamine or deferiprone (L1) is effective for the treatment of most transfused iron-loaded patients. The combination administration of deferiprone in the daytime and deferoxamine in the night appears to be universally effective in rapidly achieving negative iron balance. The cardiac iron removal effect of deferiprone increases the prospects of longer survival in beta-thalassaemia patients. New chelators have reached the stage of clinical development such as deferitrin, 1-allyl-2-methyl-3-hydroxypyrid-4-one (L1NAll) and the starch deferoxamine polymers. Deferasirox has received a conditional approval in the US under the FDA-accelerated approval regulations, but needs further verification of its efficacy and safety. Future iron chelation therapies are likely to be based on combinations of chelating drugs.
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PMID:New chelation therapies and emerging chelating drugs for the treatment of iron overload. 1650 22

Deferiprone (L1), and appropriate combinations with deferoxamine (DFO), can be used effectively for the treatment of thalassemia and other transfusional iron loading conditions. A number of experimental iron chelators such as deferasirox or ICL670 or Exjade (4-(3,5-bis (2-hydroxyphenyl)-1,2,4-triazol-1-yl)-benzoic acid), deferitrin (4,5-dihydro-2-(2,4-dihydroxyphenyl)-4-methylthiazole-4 (S)-carboxylic acid) or GT56-252, 1-allyl-2-methyl-3-hydroxypyrid-4-one or L1NAll and starch DFO polymers, are under clinical evaluation. ICL670 is the most advanced in development and appears to be effective in reducing liver iron in some patients but is overall ineffective in causing negative iron balance. It is also suspected that it is not effective in cardiac iron removal. Combination therapies using L1, DFO and new iron chelating drugs may cause higher efficacy and lower toxicity by comparison to monotherapies. However, several limitations including the high cost of the new chelating drugs may not facilitate the availability of these new treatments to the vast majority of thalassemia patients, most of whom live in developing countries.
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PMID:Future chelation monotherapy and combination therapy strategies in thalassemia and other conditions. comparison of deferiprone, deferoxamine, ICL670, GT56-252, L1NAll and starch deferoxamine polymers. 1679 57

Deferasirox (Exjade) is an oral, once-daily iron chelator widely approved for the treatment of transfusional chronic iron overload. In the EU, deferasirox is indicated in patients with beta-thalassaemia major aged > or =6 years and, in the US, in all transfusional chronic iron overload patients aged > or =2 years. Deferasirox is highly selective for iron as Fe3+. In approximately 1-year clinical trials of patients with transfusional chronic iron overload associated with beta-thalassaemia, sickle cell disease, myelodysplastic syndrome or other rare chronic anaemias, deferasirox 20 or 30 mg/kg/day had a beneficial effect on liver iron concentrations (LIC) and serum ferritin levels; tolerability issues were clinically manageable with regular patient monitoring. Although longer-term efficacy and tolerability data are required, in particular examining the prevention of iron overload-related complications and the effect of deferasirox on renal function, deferasirox is an easily administered iron chelator and is a valuable option in the management of transfusional chronic iron overload.
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PMID:Deferasirox : a review of its use in the management of transfusional chronic iron overload. 1792 85

Deferasirox (ICL670) has been shown to have rapid accessibility to intracellular labile iron. We tested the hypothesis that oral deferasirox improves arterial dysfunction in patients with beta-thalassaemia major. Nineteen thalassaemia patients, aged 23 +/- 7 years, with normal left ventricular (LV) function were treated with deferasirox at 25-35 mg/kg/d for 12 months. LV function, brachial arterial flow-mediated dilation (FMD), carotid arterial stiffness, and serum ferritin levels were determined at baseline prior to initiation, after 6 months and after 12 months of therapy. The baseline cardiovascular indices were compared with those of 17 age-matched controls. Longitudinal changes in patients during the treatment period were also determined. Compared with controls, patients had similar echocardiographic indices of LV function (all P > 0.05), while their baseline brachial FMD was reduced (P < 0.001) and carotid stiffness increased (P = 0.019). An increase in FMD (P < 0.001) and a decrease in carotid stiffness (P = 0.007) were found at 6 and 12 months follow-up. The stiffness index correlated inversely with FMD (r = -0.42, P = 0.001). Although there was an increase in ferritin level at 12 months (3303 +/- 1185 ng/ml vs. 2714 +/- 780 ng/ml at baseline, P = 0.006), no significant correlation existed between ferritin level and FMD or carotid stiffness. In conclusion, deferasirox therapy in thalassaemia patients is associated with improved arterial function.
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PMID:Effect of deferasirox (ICL670) on arterial function in patients with beta-thalassaemia major. 1831 56

The pharmacokinetics (PK) and pharmacodynamics (PD) of the once-daily, oral ironchelating agent, deferasirox (Exjade, ICL670), have been evaluated further in a Phase I, openlabel, multicenter, dose-escalation study in Japanese patients with myelodysplastic syndromes, aplastic anemia, and other anemias. Deferasirox was initially administered as a single dose of 5 (n = 6), 10 (n = 7), 20 (n = 6) or 30 (n = 7) mg/(kg day) and then after 7 days seven daily doses were administered. Linear PK (C (max) and AUC) were observed at all doses after a single dose and at steady state, and dose-dependent iron excretion was observed. Pharmacokinetic/pharmacodynamic parameters were similar to those reported in a Caucasian beta-thalassemia cohort. Following the single- and multiple-dose phases, 21 of 26 patients progressed to a 3-year extension phase of the study, where dose reductions and increases [5-30 mg/(kg day)] were allowed following safety and efficacy assessments. In the interim, 1-year data show that deferasirox was well tolerated, with generally infrequent and mild adverse events. Reductions in serum ferritin levels were observed and a negative iron balance achieved at doses of 20-30 mg/(kg day). These data suggest that deferasirox has a stable and predictable PK/PD profile, irrespective of underlying disease or race, and a predictable and manageable safety profile suitable for chronic administration.
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PMID:A safety, pharmacokinetic and pharmacodynamic investigation of deferasirox (Exjade, ICL670) in patients with transfusion-dependent anemias and iron-overload: a Phase I study in Japan. 1859 54

Deferasirox (Exjade, ICL670, CGP72670) is an iron-chelating drug for p.o. treatment of transfusional iron overload in patients with beta-thalassemia or sickle cell disease. The pharmacokinetics and disposition of deferasirox were investigated in rats. The animals received single intravenous (10 mg/kg) or p.o. (10 or 100 mg/kg) doses of 14C-radiolabeled deferasirox. Biological samples were analyzed for radioactivity (liquid scintillation counting, quantitative whole-body autoradioluminography), for deferasirox and its iron complex [high-performance liquid chromatography (HPLC)/UV], and for metabolites (HPLC with radiodetection, liquid chromatography/mass spectrometry, 1H and 13C NMR, and two-dimensional NMR techniques). At least 75% of p.o.-dosed deferasirox was absorbed. The p.o. bioavailability was 26% at the 10 mg/kg dose and showed an overproportional increase at the 100 mg/kg dose, probably because of saturation of elimination processes. Deferasirox-related radioactivity was distributed mainly to blood, excretory organs, and gastrointestinal tract. Enterohepatic recirculation of deferasirox was observed. No retention occurred in any tissue. The placental barrier was passed to a low extent. Approximately 3% of the dose was transferred into the breast milk. Excretion of deferasirox and metabolites was rapid and complete within 7 days. Key clearance processes were hepatic metabolism and biliary elimination via multidrug resistance protein 2. Deferasirox, iron complex, and metabolites were excreted largely via bile and feces (total > or = 90%). Metabolism included glucuronidation at the carboxylate group (acyl glucuronide M3) and at phenolic hydroxy groups, as well as, to a lower degree, cytochrome P450-catalyzed hydroxylations. Two hydroxylated metabolites (M1 and M2) were administered to rats and were shown not to contribute substantially to iron elimination in vivo.
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PMID:Pharmacokinetics, distribution, metabolism, and excretion of deferasirox and its iron complex in rats. 1877 80

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.
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PMID:Long-term efficacy and safety of deferasirox. 1905 55

Deferasirox is a once-daily, orally administered, tridentate iron chelator that is indicated in the treatment of iron overload resulting from regular packed red blood cell transfusions in patients with transfusion-dependent anemias, such as beta-thalassemia, sickle cell disease, myelodysplastic syndrome and other rare anemias. Randomized, controlled trials have established its efficacy to reduce liver iron concentration and serum ferritin levels to be comparable to the historic standard iron chelator, deferoxamine, which is administered as a parenteral infusion. However, deferasirox may be more effective than deferoxamine in actual clinical practice owing to the improvement in quality of life and, hence, increased compliance associated with the oral route of administration. The higher acquisition cost of deferasirox may be counterbalanced by savings in the administration cost, as well as the treatment of complications of iron overload that result from noncompliance with therapy attributable to the parenteral mode of administration. Deferasirox may also have potential as an important supplement and even an alternative to phlebotomies in nontransfusional, genetic iron overload disorders, such as hereditary hemochromatosis.
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PMID:Pharmacoeconomic benefits of deferasirox in the management of iron overload syndromes. 1967 Sep 88

The highest approved dose of deferasirox is currently 30 mg/kg per d in many countries; however, some patients require escalation above 30 mg/kg per d to achieve their therapeutic goals. This retrospective analysis investigated the efficacy (based on change in serum ferritin levels) and safety of deferasirox >30 mg/kg per d in adult and paediatric patients with transfusion-dependent anaemias, including beta-thalassaemia, sickle cell disease and the myelodysplastic syndromes. In total, 264 patients pooled from four clinical trials received doses of >30 mg/kg per d; median exposure to deferasirox >30 mg/kg per d was 36 weeks. In the overall population there was a statistically significant median decrease in serum ferritin of 440 microg/l (P < 0.0001) from pre-dose-escalation to the time-of-analysis; significant decreases were also observed in adult and paediatric patients, as well as beta-thalassaemia patients. The adverse event profile in patients who received deferasirox doses of >30 mg/kg per d was consistent with previously published data. There was no worsening of renal or liver function following dose escalation. Deferasirox >30 mg/kg per d effectively reduced iron burden to levels lower than those achieved prior to dose escalation in patients with transfusion-dependent anaemias. This has important implications for patients who are heavily transfused and may require higher doses to reduce body iron burden.
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PMID:Efficacy and safety of deferasirox doses of >30 mg/kg per d in patients with transfusion-dependent anaemia and iron overload. 1976 88


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