Deferasirox: Pharmacokinetics and clinical experience

Expert Opinion on Drug Metabolism and Toxicology

Volumn 8, Issue 1, 2012, Pages 123-134

  Galanello, Renzo ^a   Campus, Simona ^a   Origa, Raffaella ^b  

^a Osp Regionale per le Microcitemie   (Italy)

^b Unità di Ricerca Clinica Fase 1 Srl A O G   (Italy)

Author keywords

Deferasirox; Exjade ; Iron chelation; Iron overload; Myelodysplastic syndromes; Sickle cell disease; Thalassemia

Indexed keywords

ALUMINUM DERIVATIVE; CYCLOSPORIN; DEFERASIROX; DEFERIPRONE; MIDAZOLAM; SIMVASTATIN; THEOPHYLLINE;

ABDOMINAL PAIN; APLASTIC ANEMIA; BETA THALASSEMIA; COUGHING; CREATININE BLOOD LEVEL; DIARRHEA; DOSE RESPONSE; DRUG ANTAGONISM; DRUG BLOOD LEVEL; DRUG DOSE INCREASE; DRUG DOSE REGIMEN; DRUG DOSE TITRATION; DRUG EFFICACY; DRUG FORMULATION; DRUG HALF LIFE; DRUG METABOLISM; DRUG POTENTIATION; DRUG SAFETY; DRUG STRUCTURE; DRUG TOLERABILITY; DRUG WITHDRAWAL; FEVER; GASTROINTESTINAL SYMPTOM; HEART PROTECTION; HEMOCHROMATOSIS; HEMOSIDEROSIS; HUMAN; IRON CHELATION; IRON OVERLOAD; MAXIMUM PLASMA CONCENTRATION; MYELODYSPLASTIC SYNDROME; NAUSEA; RASH; RECOMMENDED DRUG DOSE; REVIEW; RHINITIS; SICKLE CELL ANEMIA; SIDE EFFECT; THALASSEMIA; THALASSEMIA MAJOR; VOMITING;

ANIMALS; BENZOIC ACIDS; BLOOD TRANSFUSION; CLINICAL TRIALS AS TOPIC; HUMANS; IRON CHELATING AGENTS; IRON OVERLOAD; IRON, DIETARY; TRIAZOLES;

EID: 84255171167     PISSN: 17425255     EISSN: 17447607     Source Type: Journal    
DOI: 10.1517/17425255.2012.640674     Document Type: Review

References (83)

1. Kohgo Y, Ikuta K, Ohtake T, et al. Body iron metabolism and pathophysiology of iron overload. Int J Hematol 2008;8:7-15
2. Hershko C, Link G, Cabantchik I. Pathophysiology of iron overload. Ann NY Acad Sci 1998;850:191-201 (Pubitemid 28369759)
3. Pippard MJ, Callender ST, Warner GT, Weatherall DJ. Iron absorption and loading in beta-thalassaemia intermedia. Lancet 1979;2:819-21 (Pubitemid 10205108)
4. Pootrakul P, Huebers HA, Finch CA, et al. Iron metabolism in thalassemia. Birth Defects Orig Artic Ser 1988;23:3-8
5. Borgna-Pignatti C, Rugolotto S, De Stefano P, et al. Survival and disease complications in thalassemia major. Ann NY Acad Sci 1998;850:227-31 (Pubitemid 28369763)
6. Kattamis C, Liakopoulou T, Kattamis A. Growth and development in children with thalassaemia major. Acta Paediatr Scand Suppl 1990;366:111-17 (Pubitemid 20188340)
7. Ladis V, Chouliaras G, Berdousi H, et al. Longitudinal study of survival and causes of death in patients with thalassemia major in Greece. Ann NY Acad Sci 2005;1054:445-50 (Pubitemid 43031054)
8. Low LC. Growth of children with beta-thalassemia major. Indian J Pediatr 2005;72:159-64
9. Modell B, Khan M, Darlison M. Survival in beta-thalassaemia major in the UK: data from the UK Thalassaemia Register. Lancet 2000;355:2051-2 (Pubitemid 30339248)
10. Desferal (deferoxamine) Basic Prescribing Information. 2010. Available from: http://www.pharma.us.novartis.com/product/pi/pdf/desferal.pdf
11. Cappellini MD, Pattoneri P. Oral iron chelators. Annu Rev Med 2009;60:25-38
12. Cohen AR. New advances in iron chelation therapy. Hematology Am Soc Hematol Educ Program 2006;2006(1):42-7
13. Neufeld EJ. Oral chelators deferasirox and deferiprone for transfusional iron overload in thalassemia major: new data, new questions. Blood 2006;107:3436-41
14. Ferriprox prescribing information. 2007. Available from: http://www.ferriprox.com
15. Westwood M, Anderson LJ, Pennell DJ. Treatment of cardiac iron overload in thalassemia major. Haematologica 2003;88:481-2 (Pubitemid 36648434)
16. Borgna-Pignatti C, Cappellini MD, De Stefano P, et al. Cardiac morbidity and mortality in deferoxamine-or deferiprone-treated patients with thalassemia major. Blood 2006;107:3733-7
17. Pennell DJ, Berdoukas V, Karagiorga M, et al. Randomized controlled trial of deferiprone or deferoxamine in beta-thalassemia major patients with asymptomatic myocardial siderosis. Blood 2006;107:3738-44
18. Piga A, Gaglioti C, Fogliacco E, Tricta F. Comparative effects of deferiprone and deferoxamine on survival and cardiac disease in patients with thalassemia major: a retrospective analysis. Haematologica 2003;88:489-96 (Pubitemid 36648438)
19. Origa R, Bina P, Agus A, et al. Combined therapy with deferiprone and desferrioxamine in thalassemia major. Haematologica 2005;90:1309-14 (Pubitemid 41503645)
20. Kattamis A, Ladis V, Berdousi H, et al. Iron chelation treatment with combined therapy with deferiprone and deferoxamine: a 12-month trial. Blood Cells Mol Dis 2006;36:21-5 (Pubitemid 43061483)
21. Tanner MA, Galanello R, Dessi C, et al. A randomized, placebo-controlled, double-blind trial of the effect of combined therapy with deferoxamine and deferiprone on myocardial iron in thalassemia major using cardiovascular magnetic resonance. Circulation 2007;115:1876-84 (Pubitemid 46598901)
22. Tanner MA, Galanello R, Dessi C, et al. Combined chelation therapy in thalassemia major for the treatment of severe myocardial siderosis with left ventricular dysfunction. J Cardiovasc Magn Reson 2008;10:12
23. Farmaki K, Tzoumari I, Pappa C, et al. Normalisation of total body iron load with very intensive combined chelation reverses cardiac and endocrine complications of thalassaemia major. Br J Haematol 2010;148:466-75
24. EXJADE (deferasirox) US Prescribing Information. 2011. Available from: http://www.pharma.us.novartis.com/product/pi/pdf/exjade.pdf.
25. Rienhoff HY Jr, Viprakasit V, Tay L, et al. A phase 1 dose-escalation study: safety, tolerability, and pharmacokinetics of FBS0701, a novel oral iron chelator for the treatment of transfusional iron overload. Haematologica 2011;96:521-5
26. El Ouagari K, Migliaccio-Walle K, Lau H, Bozkaya D. Cost-effectiveness of deferasirox in lower-risk myelodysplastic syndrome (MDS) in Canada [abstract 343]. Leuk Res 2011;35:S137-8
27. Calabro A, Delea TE, Sofrygin O, et al. Cost-effectiveness of once-daily oral chelation therapy with deferasirox versus infusional deferoxamine in transfusion-dependent thalassemic patients: a Brazilian perspective. Haematologica 2006;91(Suppl 1):abstract 804
28. Delea TE, Thomas SK, Baladi J, Phatak PD. Cost-effectiveness analysis of oral iron chelation therapy with deferasirox (Exjade, ICL670) versus infusional chelation therapy with deferoxamine in patients with transfusion-dependent myelodysplastic syndrome. Blood 2005;106(11):abstract 5585
29. Glickstein H, El RB, Shvartsman M, Cabantchik ZI. Intracellular labile iron pools as direct targets of iron chelators: a fluorescence study of chelator action in living cells. Blood 2005;106:3242-50 (Pubitemid 41565925)
30. Glickstein H, El BR, Link G, et al. Action of chelators in iron-loaded cardiac cells: accessibility to intracellular labile iron and functional consequences. Blood 2006;108:3195-203
31. Daar S, Pathare A, Nick H, et al. Reduction in labile plasma iron during treatment with deferasirox, a once-daily oral iron chelator, in heavily iron-overloaded patients with beta-thalassaemia. Eur J Haematol 2009;82:454-7
32. Nick H, Wong A, Acklin P, et al. ICL670A: preclinical profile. Adv Exp Med Biol 2002;509:185-203 (Pubitemid 37526718)
33. Nick H, Acklin P, Lattmann R, et al. Development of tridentate iron chelators: from desferrithiocin to ICL670. Curr Med Chem 2003;10:1065-76 (Pubitemid 36582249)
34. Nick H. Deferasirox (Exjade, ICL670) preclinical overview. Semin Hematol 2007;44:S12-15 (Pubitemid 46754343)
35. Waldmeier F, Bruin GJ, Glaenzel U, et al. Pharmacokinetics, metabolism, and disposition of deferasirox in beta-thalassemic patients with transfusion-dependent iron overload who are at pharmacokinetic steady state. Drug Metab Dispos 2010;38:808-16
36. Piga A, Galanello R, Forni GL, et al. 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 2006;91:873-80 (Pubitemid 44023139)
37. Galanello R, Origa R. Once-daily oral deferasirox for the treatment of transfusional iron overload. Expert Rev Clin Pharmacol 2008;1:231-40
38. Galanello R, Piga A, Alberti D, et al. Safety, tolerability, and pharmacokinetics of ICL670, a new orally active iron-chelating agent in patients with transfusion-dependent iron overload due to beta-thalassemia. J Clin Pharmacol 2003;43:565-72 (Pubitemid 36613115)
39. Galanello R, Piga A, Forni GL, et al. Phase II clinical evaluation of deferasirox, a once-daily oral chelating agent, in pediatric patients with beta-thalassemia major. Haematologica 2006;91:1343-51 (Pubitemid 44569807)
40. Cappellini MD, Cohen A, Piga A, et al. A phase 3 study of deferasirox (ICL670), a once-daily oral iron chelator, in patients with beta-thalassemia. Blood 2006;107:3455-62
41. Chang HH, Lu MY, Liao YM, et al. Improved efficacy and tolerability of oral deferasirox by twice-daily dosing for patients with transfusion-dependent beta-thalassemia. Pediatr Blood Cancer 2011;56:420-4
42. Chirnomas D, Smith AL, Braunstein J, et al. Deferasirox pharmacokinetics in patients with adequate versus inadequate response. Blood 2009;114:4009-13
43. Chirnomas D, Yakhkind A, Paley CS, Neufeld EJ. Strategies to improve iron chelation in thalassemia patients poorly responsive to deferasirox. Blood 2010;116(21):abstract 4279
44. Skerjanec A, Wang J, Maren K, Rojkjaer L. Investigation of the pharmacokinetic interactions of deferasirox, a once-daily oral iron chelator, with midazolam, rifampin, and repaglinide in healthy volunteers. J Clin Pharmacol 2010;50:205-13
45. Galanello R, Piga A, Cappellini MD, et al. Effect of food, type of food, and time of food intake on deferasirox bioavailability: recommendations for an optimal deferasirox administration regimen. J Clin Pharmacol 2008;48:428-35 (Pubitemid 351389109)
46. Sechaud R, Dutreix C, Balez S, et al. Relative bioavailability of deferasirox tablets administered without dispersion and dispersed in various drinks. Int J Clin Pharmacol Ther 2008;46:102-8 (Pubitemid 351233796)
47. Taher A, Cappellini MD, Vichinsky E, et al. Efficacy and safety of deferasirox doses of > 30 mg/kg per d in patients with transfusion-dependent anaemia and iron overload. Br J Haematol 2009;147:752-9
48. Cappellini MD, Porter JB, El-Beshlawy A, et al. Tailoring iron chelation by iron intake and serum ferritin trends: the prospective multicenter EPIC study of deferasirox in 1744 patients with various transfusion-dependent anemias. Haematologica 2010;95:557-66
49. Gattermann N. Guidelines on iron chelation therapy in patients with myelodysplastic syndromes and transfusional iron overload. Leuk Res 2007;31(Suppl 3):S10-15 (Pubitemid 350137502)
50. Thalassaemia International Federation. Guidelines for the clinical management of thalassaemia, 2nd Revised Edition. 2008. Available from: http://www thalassaemia org cy/pdf/Guidelines-2nd-revised-edition-EN pdf
51. Cappellini MD, Bejaoui M, Agaoglu L, et al. Iron chelation with deferasirox in adult and pediatric patients with thalassemia major: efficacy and safety during 5 years follow-up. Blood 2011;118:884-93
52. Gattermann N, Finelli C, Della Porta M, et al. Deferasirox in iron-overloaded patients with transfusion-dependent myelodysplastic syndromes: results from the large 1-year EPIC study. Leuk Res 2010;34:1143-50
53. Lee J-W, Yoon S-S, Shen ZX, et al. Iron chelation therapy with deferasirox in patients with aplastic anemia: A subgroup analysis of 116 patients from the EPIC trial. Blood 2010;116:2448-54
54. Porter J, Galanello R, Saglio G, et al. Relative response of patients with myelodysplastic syndromes and other transfusion-dependent anaemias to deferasirox (ICL670): a 1-yr prospective study. Eur J Haematol 2008;80:168-76
55. Anderson LJ, Holden S, Davis B, et al. Cardiovascular T2-star (T2*) magnetic resonance for the early diagnosis of myocardial iron overload. Eur Heart J 2001;22:2171-9 (Pubitemid 33139463)
56. Pennell D, Porter JB, Cappellini MD, et al. Continued improvement and normalization of myocardial T2*in patients with beta-thalassemia major treated with deferasirox (Exjade) for up to 3 years. Blood 2010;116(21):abstract 4276
57. Pennell DJ, Porter JB, Cappellini MD, et al. Continued improvement in myocardial T2*over 2 years of deferasirox therapy in beta-thalassemia major patients with cardiac iron overload. Haematologica 2011;96:48-54
58. Pennell DJ, Porter JB, Cappellini MD, et al. Efficacy of deferasirox in reducing and preventing cardiac iron overload in beta-thalassemia. Blood 2010;115:2364-71
59. Galanello R, Agus A, Campus S, et al. Combined iron chelation therapy. Ann NY Acad Sci 2010;1202:79-86
60. Lal A, Sweeters N, Ng V, et al. Combined chelation therapy with deferasirox and deferoxamine in transfusion-dependent thalassemia. Blood 2010;116(21):abstract 4269
61. Ghoti H, Fibach E, Merkel D, et al. Changes in parameters of oxidative stress and free iron biomarkers during treatment with deferasirox in iron-overloaded patients with myelodysplastic syndromes. Haematologica 2010;95:1433-4
62. Rose C, Brechignac S, Vassilief D, et al. Does iron chelation therapy improve survival in regularly transfused lower risk MDS patients? A multicenter study by the GFM. Leuk Res 2010;34:864-70
63. Fox F, Kundgen A, Nachtkamp K, et al. Matched-pair analysis of 186 MDS patients receiving iron chelation therapy or transfusion therapy only. Blood 2009;114(22):abstract 1747
64. Vichinsky E, Bernaudin F, Forni GL, et al. Long-term safety and efficacy of deferasirox (Exjade) for up to 5 years in transfusional iron-overloaded patients with sickle cell disease. Br J Haematol 2011;154:387-97
65. Aydinok Y, Agaoglu L, Bejaoui M, et al. Growth and development of paediatric patients with beta-thalassaemia treated with deferasirox for up to 5 years. Haematologica 2010;95(Suppl 2):abstract 1040
66. Taher A, El-Beshlawy A, Elalfy MS, et al. Efficacy and safety of deferasirox, an oral iron chelator, in heavily iron-overloaded patients with betathalassaemia: the ESCALATOR study. Eur J Haematol 2009;82:458-65
67. Taher A, Elalfy MS, Al ZK, et al. Importance of optimal dosing >/= 30 mg/kg/d during deferasirox treatment: 2.7-year follow-up from the ESCALATOR study in patients with beta-thalassaemia. Eur J Haematol 2011;87:355-65
68. Ladis V, Berdousi H, Gotsis E, Kattamis A. Deferasirox administration for the treatment of non-transfusional iron overload in patients with thalassaemia intermedia. Br J Haematol 2010;151:504-8
69. Phatak P, Brissot P, Wurster M, et al. A phase 1/2, dose-escalation trial of deferasirox for the treatment of iron overload in HFE-related hereditary hemochromatosis. Hepatology 2010;52:1671-9
70. Voskaridou E, Plata E, Douskou M, et al. Treatment with deferasirox (Exjade) effectively decreases iron burden in patients with thalassaemia intermedia: results of a pilot study. Br J Haematol 2010;148:332-4
71. Deugnier Y, Turlin B, Ropert M, et al. Improvement in liver pathology of patients with beta-thalassemia treated with deferasirox for at least 3 years. Gastroenterology 2011;141(4):1202-11
72. Gattermann N, Finelli C, Porta MD, et al. Hematologic responses in myelodysplastic syndromes (MDS) patients treated with deferasirox: an EPIC post-hoc analysis using International Working Group (IWG) 2006 criteria. Blood 2010;116(21):abstract 2912
73. Piga A, Fracchia S, Lai ME, et al. Effect of deferasirox on renal haemodynamics in patients with beta-thalassaemia: first interim analysis. Haematologica 2010;95(Suppl 2):abstract 1798
74. Schmid M, Cappellini MD, Porter JB, et al. Safety of deferasirox (Exjade) in myelodysplastic syndromes (MDS) and non-MDS patients with transfusional iron overload: a pooled analysis focusing on renal function. Blood 2009;114(22):abstract 1768
75. Even-Or E, Becker-Cohen R, Miskin H. Deferasirox treatment may be associated with reversible renal Fanconi syndrome. Am J Hematol 2010;85:132-4
76. Grange S, Bertrand DM, Guerrot D, et al. Acute renal failure and Fanconi syndrome due to deferasirox. Nephrol Dial Transplant 2010;25:2376-8
77. Rafat C, Fakhouri F, Ribeil JA, et al. Fanconi syndrome due to deferasirox. Am J Kidney Dis 2009;54:931-4
78. Rheault MN, Bechtel H, Neglia JP, Kashtan CE. Reversible Fanconi syndrome in a pediatric patient on deferasirox. Pediatr Blood Cancer 2011;56:674-6
79. Wei HY, Yang CP, Cheng CH, Lo FS. Fanconi syndrome in a patient with beta-thalassemia major after using deferasirox for 27 months. Transfusion 2011;51:949-54
80. Yacobovich J, Stark P, Barzilai-Birenbaum S, et al. Acquired proximal renal tubular dysfunction in beta-thalassemia patients treated with deferasirox. J Pediatr Hematol Oncol 2010;32:564-7
81. Piga A, Kebaili K, Galanello R, et al. Cumulative efficacy and safety of 5-year deferasirox (Exjade) treatment in pediatric patients with thalassemia major: a phase II multicenter prospective trial. Blood 2008;112(11):abstract 5413
82. Vichinsky E, Onyekwere O, Porter J, et al. A randomized comparison of deferasirox versus deferoxamine for the treatment of transfusional iron overload in sickle cell disease. Br J Haematol 2007;136:501-8 (Pubitemid 46046309)
83. Porter JB, Lin KH, Beris P, et al. Response of iron overload to deferasirox in rare transfusion-dependent anaemias: equivalent effects on serum ferritin and labile plasma iron for haemolytic or production anaemias. Eur J Haematol 2011;87:338-48