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Effectiveness and safety of ICL670 in iron-loaded patients with thalassaemia: a randomised, double-blind, placebo-controlled, dose-escalation trial

Transfusional iron overload is a potentially fatal complication of the treatment of thalassaemia. We aimed to investigate short-term efficacy, pharmacokinetic/pharma-codynamic (PK/PD) relations, and safety of ICL670, a novel, tridentate, orally active iron chelator. We enrolled 24 patients and divid... Full description

Journal Title: The Lancet (British edition) 2003-05-10, Vol.361 (9369), p.1597-1602
Main Author: Nisbet-Brown, Eric
Other Authors: Olivieri, Nancy F , Giardina, Patricia J , Grady, Robert W , Neufeld, Ellis J , Séchaud, Romain , Krebs-Brown, Axel J , Anderson, Judith R , Alberti, Daniele , Sizer, Kurt C , Nathan, David G
Format: Electronic Article Electronic Article
Language: English
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Quelle: Alma/SFX Local Collection
Publisher: London: Elsevier Ltd
ID: ISSN: 0140-6736
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title: Effectiveness and safety of ICL670 in iron-loaded patients with thalassaemia: a randomised, double-blind, placebo-controlled, dose-escalation trial
format: Article
creator:
  • Nisbet-Brown, Eric
  • Olivieri, Nancy F
  • Giardina, Patricia J
  • Grady, Robert W
  • Neufeld, Ellis J
  • Séchaud, Romain
  • Krebs-Brown, Axel J
  • Anderson, Judith R
  • Alberti, Daniele
  • Sizer, Kurt C
  • Nathan, David G
subjects:
  • Abridged Index Medicus
  • Adolescent
  • Adult
  • Analysis
  • Anemias. Hemoglobinopathies
  • Area Under Curve
  • Benzoates - administration & dosage
  • Benzoates - pharmacokinetics
  • Benzoates - therapeutic use
  • beta-Thalassemia - complications
  • beta-Thalassemia - drug therapy
  • Biological and medical sciences
  • Blood
  • Care and treatment
  • Chelating agents
  • Children & youth
  • Clinical trials
  • Collaboration
  • Deferoxamine - therapeutic use
  • Diseases of red blood cells
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Drug dosages
  • Drug toxicity and drugs side effects treatment
  • Erythrocytes
  • Evaluation
  • Evidence-based medicine
  • Excretion
  • Exposure
  • Female
  • Ferritins - blood
  • Hematologic and hematopoietic diseases
  • Humans
  • Intestinal Absorption
  • Iron
  • Iron - urine
  • Iron Overload - complications
  • Iron Overload - drug therapy
  • Laboratories
  • Male
  • Medical sciences
  • Miscellaneous (drug allergy, mutagens, teratogens...)
  • Patients
  • Pharmaceuticals
  • Pharmacokinetics
  • Pharmacology
  • Pharmacology. Drug treatments
  • Plasma
  • Research centers
  • Safety
  • Skin
  • Skin diseases
  • Thalassemia
  • Triazoles - administration & dosage
  • Triazoles - pharmacokinetics
  • Triazoles - therapeutic use
  • Urine
ispartof: The Lancet (British edition), 2003-05-10, Vol.361 (9369), p.1597-1602
description: Transfusional iron overload is a potentially fatal complication of the treatment of thalassaemia. We aimed to investigate short-term efficacy, pharmacokinetic/pharma-codynamic (PK/PD) relations, and safety of ICL670, a novel, tridentate, orally active iron chelator. We enrolled 24 patients and divided them into three cohorts consisting of a minimum of seven individuals. Patients were admitted to a metabolic unit and consumed a diet with a defined content of iron. Two patients in each cohort were randomly allocated placebo. Five or more patients received one daily dose of ICL670 at 10, 20, or 40 mg kg−1 day−1, from day 1 to 12. Net iron excretion (NIE) was measured between days 1 and 12. Primary objectives included assessment of safety and tolerability (measured by adverse events and clinical laboratory monitoring), pharmacokinetics (measured as drug and drug-iron complex), and cumulative net iron excretion (measured by faecal and urine output minus food input). Analysis was for efficacy. ICL670 was absorbed promptly and was detectable in the blood for 24 h. Exposure (area under the curve of plasma concentration) to ICL670 at pharmacokinetic steady state was proportional to dose. All three doses resulted in positive NIE. The NIE achieved at 20 mg kg−1day−1 would prevent net iron accumulation in most patients transfused with 12–15 mL packed red-blood-cells kg−1 month−1, equivalent to 0·3–0·5 mg iron kg−1 day−1. A linear relation (PK/PD) was recorded between exposure to ICL670 and total iron excretion, by contrast with placebo (r2=0·54, p
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 0140-6736
fulltext: fulltext
issn:
  • 0140-6736
  • 1474-547X
url: Link


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titleEffectiveness and safety of ICL670 in iron-loaded patients with thalassaemia: a randomised, double-blind, placebo-controlled, dose-escalation trial
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creatorNisbet-Brown, Eric ; Olivieri, Nancy F ; Giardina, Patricia J ; Grady, Robert W ; Neufeld, Ellis J ; Séchaud, Romain ; Krebs-Brown, Axel J ; Anderson, Judith R ; Alberti, Daniele ; Sizer, Kurt C ; Nathan, David G
creatorcontribNisbet-Brown, Eric ; Olivieri, Nancy F ; Giardina, Patricia J ; Grady, Robert W ; Neufeld, Ellis J ; Séchaud, Romain ; Krebs-Brown, Axel J ; Anderson, Judith R ; Alberti, Daniele ; Sizer, Kurt C ; Nathan, David G
descriptionTransfusional iron overload is a potentially fatal complication of the treatment of thalassaemia. We aimed to investigate short-term efficacy, pharmacokinetic/pharma-codynamic (PK/PD) relations, and safety of ICL670, a novel, tridentate, orally active iron chelator. We enrolled 24 patients and divided them into three cohorts consisting of a minimum of seven individuals. Patients were admitted to a metabolic unit and consumed a diet with a defined content of iron. Two patients in each cohort were randomly allocated placebo. Five or more patients received one daily dose of ICL670 at 10, 20, or 40 mg kg−1 day−1, from day 1 to 12. Net iron excretion (NIE) was measured between days 1 and 12. Primary objectives included assessment of safety and tolerability (measured by adverse events and clinical laboratory monitoring), pharmacokinetics (measured as drug and drug-iron complex), and cumulative net iron excretion (measured by faecal and urine output minus food input). Analysis was for efficacy. ICL670 was absorbed promptly and was detectable in the blood for 24 h. Exposure (area under the curve of plasma concentration) to ICL670 at pharmacokinetic steady state was proportional to dose. All three doses resulted in positive NIE. The NIE achieved at 20 mg kg−1day−1 would prevent net iron accumulation in most patients transfused with 12–15 mL packed red-blood-cells kg−1 month−1, equivalent to 0·3–0·5 mg iron kg−1 day−1. A linear relation (PK/PD) was recorded between exposure to ICL670 and total iron excretion, by contrast with placebo (r2=0·54, p<0·0001). Skin rashes were noted in four patients treated at 20 and 40 mg kg−1 day−1, and one patient also developed grade 2 transaminitis. ICL670 given once daily at 20 mg/kg seems to be an effective orally active iron chelator and is reasonably well tolerated. Long-term studies are now necessary to establish the practical contribution of this drug.
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0ISSN: 0140-6736
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languageeng
publisherLondon: Elsevier Ltd
subjectAbridged Index Medicus ; Adolescent ; Adult ; Analysis ; Anemias. Hemoglobinopathies ; Area Under Curve ; Benzoates - administration & dosage ; Benzoates - pharmacokinetics ; Benzoates - therapeutic use ; beta-Thalassemia - complications ; beta-Thalassemia - drug therapy ; Biological and medical sciences ; Blood ; Care and treatment ; Chelating agents ; Children & youth ; Clinical trials ; Collaboration ; Deferoxamine - therapeutic use ; Diseases of red blood cells ; Dose-Response Relationship, Drug ; Double-Blind Method ; Drug dosages ; Drug toxicity and drugs side effects treatment ; Erythrocytes ; Evaluation ; Evidence-based medicine ; Excretion ; Exposure ; Female ; Ferritins - blood ; Hematologic and hematopoietic diseases ; Humans ; Intestinal Absorption ; Iron ; Iron - urine ; Iron Overload - complications ; Iron Overload - drug therapy ; Laboratories ; Male ; Medical sciences ; Miscellaneous (drug allergy, mutagens, teratogens...) ; Patients ; Pharmaceuticals ; Pharmacokinetics ; Pharmacology ; Pharmacology. Drug treatments ; Plasma ; Research centers ; Safety ; Skin ; Skin diseases ; Thalassemia ; Triazoles - administration & dosage ; Triazoles - pharmacokinetics ; Triazoles - therapeutic use ; Urine
ispartofThe Lancet (British edition), 2003-05-10, Vol.361 (9369), p.1597-1602
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1Olivieri, Nancy F
2Giardina, Patricia J
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4Neufeld, Ellis J
5Séchaud, Romain
6Krebs-Brown, Axel J
7Anderson, Judith R
8Alberti, Daniele
9Sizer, Kurt C
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0Effectiveness and safety of ICL670 in iron-loaded patients with thalassaemia: a randomised, double-blind, placebo-controlled, dose-escalation trial
1The Lancet (British edition)
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descriptionTransfusional iron overload is a potentially fatal complication of the treatment of thalassaemia. We aimed to investigate short-term efficacy, pharmacokinetic/pharma-codynamic (PK/PD) relations, and safety of ICL670, a novel, tridentate, orally active iron chelator. We enrolled 24 patients and divided them into three cohorts consisting of a minimum of seven individuals. Patients were admitted to a metabolic unit and consumed a diet with a defined content of iron. Two patients in each cohort were randomly allocated placebo. Five or more patients received one daily dose of ICL670 at 10, 20, or 40 mg kg−1 day−1, from day 1 to 12. Net iron excretion (NIE) was measured between days 1 and 12. Primary objectives included assessment of safety and tolerability (measured by adverse events and clinical laboratory monitoring), pharmacokinetics (measured as drug and drug-iron complex), and cumulative net iron excretion (measured by faecal and urine output minus food input). Analysis was for efficacy. ICL670 was absorbed promptly and was detectable in the blood for 24 h. Exposure (area under the curve of plasma concentration) to ICL670 at pharmacokinetic steady state was proportional to dose. All three doses resulted in positive NIE. The NIE achieved at 20 mg kg−1day−1 would prevent net iron accumulation in most patients transfused with 12–15 mL packed red-blood-cells kg−1 month−1, equivalent to 0·3–0·5 mg iron kg−1 day−1. A linear relation (PK/PD) was recorded between exposure to ICL670 and total iron excretion, by contrast with placebo (r2=0·54, p<0·0001). Skin rashes were noted in four patients treated at 20 and 40 mg kg−1 day−1, and one patient also developed grade 2 transaminitis. ICL670 given once daily at 20 mg/kg seems to be an effective orally active iron chelator and is reasonably well tolerated. Long-term studies are now necessary to establish the practical contribution of this drug.
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1Adolescent
2Adult
3Analysis
4Anemias. Hemoglobinopathies
5Area Under Curve
6Benzoates - administration & dosage
7Benzoates - pharmacokinetics
8Benzoates - therapeutic use
9beta-Thalassemia - complications
10beta-Thalassemia - drug therapy
11Biological and medical sciences
12Blood
13Care and treatment
14Chelating agents
15Children & youth
16Clinical trials
17Collaboration
18Deferoxamine - therapeutic use
19Diseases of red blood cells
20Dose-Response Relationship, Drug
21Double-Blind Method
22Drug dosages
23Drug toxicity and drugs side effects treatment
24Erythrocytes
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29Female
30Ferritins - blood
31Hematologic and hematopoietic diseases
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33Intestinal Absorption
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36Iron Overload - complications
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43Pharmaceuticals
44Pharmacokinetics
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46Pharmacology. Drug treatments
47Plasma
48Research centers
49Safety
50Skin
51Skin diseases
52Thalassemia
53Triazoles - administration & dosage
54Triazoles - pharmacokinetics
55Triazoles - therapeutic use
56Urine
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titleEffectiveness and safety of ICL670 in iron-loaded patients with thalassaemia: a randomised, double-blind, placebo-controlled, dose-escalation trial
authorNisbet-Brown, Eric ; Olivieri, Nancy F ; Giardina, Patricia J ; Grady, Robert W ; Neufeld, Ellis J ; Séchaud, Romain ; Krebs-Brown, Axel J ; Anderson, Judith R ; Alberti, Daniele ; Sizer, Kurt C ; Nathan, David G
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7Benzoates - pharmacokinetics
8Benzoates - therapeutic use
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55Triazoles - therapeutic use
56Urine
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abstractTransfusional iron overload is a potentially fatal complication of the treatment of thalassaemia. We aimed to investigate short-term efficacy, pharmacokinetic/pharma-codynamic (PK/PD) relations, and safety of ICL670, a novel, tridentate, orally active iron chelator. We enrolled 24 patients and divided them into three cohorts consisting of a minimum of seven individuals. Patients were admitted to a metabolic unit and consumed a diet with a defined content of iron. Two patients in each cohort were randomly allocated placebo. Five or more patients received one daily dose of ICL670 at 10, 20, or 40 mg kg−1 day−1, from day 1 to 12. Net iron excretion (NIE) was measured between days 1 and 12. Primary objectives included assessment of safety and tolerability (measured by adverse events and clinical laboratory monitoring), pharmacokinetics (measured as drug and drug-iron complex), and cumulative net iron excretion (measured by faecal and urine output minus food input). Analysis was for efficacy. ICL670 was absorbed promptly and was detectable in the blood for 24 h. Exposure (area under the curve of plasma concentration) to ICL670 at pharmacokinetic steady state was proportional to dose. All three doses resulted in positive NIE. The NIE achieved at 20 mg kg−1day−1 would prevent net iron accumulation in most patients transfused with 12–15 mL packed red-blood-cells kg−1 month−1, equivalent to 0·3–0·5 mg iron kg−1 day−1. A linear relation (PK/PD) was recorded between exposure to ICL670 and total iron excretion, by contrast with placebo (r2=0·54, p<0·0001). Skin rashes were noted in four patients treated at 20 and 40 mg kg−1 day−1, and one patient also developed grade 2 transaminitis. ICL670 given once daily at 20 mg/kg seems to be an effective orally active iron chelator and is reasonably well tolerated. Long-term studies are now necessary to establish the practical contribution of this drug.
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pubElsevier Ltd
pmid12747879
doi10.1016/S0140-6736(03)13309-0