Do we need more iron-chelating drugs?

Abstract

Eric Nisbet-Brown and co-workers (May 10, p 1597)1Nisbet-Brown E Olivieri NF Giardina PJ et al.Effectiveness and safety of ICL670 in iron-loaded patients with thalassaemia: a randomised, double-blind, placebo-controlled, dose-escalation trial.Lancet. 2003; 361: 1597-1602Summary Full Text Full Text PDF PubMed Scopus (308) Google Scholar suggest that the initial clinical trial results of the iron-chelating drug ICL670 (4-[3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl]-benzoic acid) are encouraging, although long-term safety and efficacy studies are needed. They also indicate that at the tolerated dose of 20 mg kg−1 day−1, ICL670 is an effective orally active iron chelator, because net iron excretion is just within the range of iron intake from standard transfusion regimens of 12–15 mL packed red-blood-cells kg−1 month−1. However, in the placebo group, mean net iron excretion is above zero and if this is taken into account ICL670 is not within the effective range of iron chelation.Nisbet-Brown and colleagues also suggest that deferiprone is ineffective and that ICL670 at 20 mg kg−1 day−1 is more effective than deferoxamine. However, even at the highest dose of ICL670 used (40 mg kg−1 day−1), the mean daily iron excretion achieved is 23 mg for a 50 kg man, which is higher than 15 mg achieved at the 20 mg kg−1 day−1 dose, but much lower than that achieved with deferiprone or deferox-amine in patients who have thalas-saemia, with mean daily iron excretion of 27 mg and 42 mg at doses of deferiprone of 75 mg/kg and 100 mg/kg, respectively.2Olivieri NF Koren G Hermann C et al.Comparison of iron chelator L1 and desferrioxamine in iron loaded patients.Lancet. 1990; 336: 1275-1279Summary PubMed Scopus (142) Google Scholar, 3Agarwal MB Gupte SS Viswanathan C et al.Long term assessment and safety of L1, an oral iron chelator, in transfusion dependent thalassaemia: Indian trial.BrJHaematol. 1992; 82: 460-466Crossref PubMed Scopus (168) Google Scholar The different pharmacokinetic profile of ICL670, including its slow rate of plasma clearance of half life of 12–16 h, limits the prospects of repeated administration and, consequently, its efficacy for iron removal.4Kontoghiorghes GJ Neocleous K Kolnagou A Benefits and risks of deferiprone in iron overload in thalassaemia and other conditions. Comparison of epidemiological and therapeutic aspects with deferoxamine.Drug Safety. 2003; 26: 553-584Crossref PubMed Scopus (97) Google Scholar The ferrokinetic profile of ICL670, which results mainly in an increase of faecal iron excretion, and its slow clearance from blood suggests accumulation of the drug, its metabolites, and iron complexes in lipid-soluble compartments of serum proteins and tissues and the inability of iron complexes to be cleared through the kidneys. Such properties increase the likelihood of toxic effects, similar to those of 8-hydroxyquinoline, which has similar lipophilicity to ICL670.5Yamamoto RS Williams GM Frankel HH Weisburger JH 8-Hydroxyquinoline: chronic toxicity and inhibitory effect on the carcinogenicity of N-2-fluorenylacetamide.Toxic Appl Pharmacol. 1971; 19: 687-698Crossref PubMed Scopus (50) Google Scholar Lipophilic chelators similar to ICL670, including 8-hydroxyquinoline, also cause an increase in the absorption of iron.4Kontoghiorghes GJ Neocleous K Kolnagou A Benefits and risks of deferiprone in iron overload in thalassaemia and other conditions. Comparison of epidemiological and therapeutic aspects with deferoxamine.Drug Safety. 2003; 26: 553-584Crossref PubMed Scopus (97) Google Scholar, 5Yamamoto RS Williams GM Frankel HH Weisburger JH 8-Hydroxyquinoline: chronic toxicity and inhibitory effect on the carcinogenicity of N-2-fluorenylacetamide.Toxic Appl Pharmacol. 1971; 19: 687-698Crossref PubMed Scopus (50) Google Scholar A major drawback in understanding the ferrokinetic and pharmacodynamic characteristics of ICL670 is the absence of information about the isolation and characterisation of the metabolite(s) of ICL670, some of which may have iron-chelating properties. These characteristics may explain several unexplained observations in relation to unsaturated iron binding capacity (UIBC) in serum, why the results for total exposure to the drug as estimated by the area under the curve (AUC) were not proportional to the ICL670 dose; and why plasma concentrations of the iron complex Fe-[ICL670]2 were not related to dose. Another concern about ICL670 is the cost to patients—only if it is cheaper than deferoxamine and deferiprone will it benefit most of the patients with thalassaemia in developing countries.4Kontoghiorghes GJ Neocleous K Kolnagou A Benefits and risks of deferiprone in iron overload in thalassaemia and other conditions. Comparison of epidemiological and therapeutic aspects with deferoxamine.Drug Safety. 2003; 26: 553-584Crossref PubMed Scopus (97) Google ScholarThe introduction of new iron-chelating drugs may ultimately improve iron-chelation therapy for patients with thalassaemia and other disorders. As with deferiprone or deferoxamine, patients with thalassaemia are expected to have variable response with respect to ICL670. Protocols to select the most effective and least toxic drug, or drug combinations, for each patient may increase the therapeutic benefits for patients who do not respond to, or have toxic side-effects from, a single chelating drug. Eric Nisbet-Brown and co-workers (May 10, p 1597)1Nisbet-Brown E Olivieri NF Giardina PJ et al.Effectiveness and safety of ICL670 in iron-loaded patients with thalassaemia: a randomised, double-blind, placebo-controlled, dose-escalation trial.Lancet. 2003; 361: 1597-1602Summary Full Text Full Text PDF PubMed Scopus (308) Google Scholar suggest that the initial clinical trial results of the iron-chelating drug ICL670 (4-[3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl]-benzoic acid) are encouraging, although long-term safety and efficacy studies are needed. They also indicate that at the tolerated dose of 20 mg kg−1 day−1, ICL670 is an effective orally active iron chelator, because net iron excretion is just within the range of iron intake from standard transfusion regimens of 12–15 mL packed red-blood-cells kg−1 month−1. However, in the placebo group, mean net iron excretion is above zero and if this is taken into account ICL670 is not within the effective range of iron chelation. Nisbet-Brown and colleagues also suggest that deferiprone is ineffective and that ICL670 at 20 mg kg−1 day−1 is more effective than deferoxamine. However, even at the highest dose of ICL670 used (40 mg kg−1 day−1), the mean daily iron excretion achieved is 23 mg for a 50 kg man, which is higher than 15 mg achieved at the 20 mg kg−1 day−1 dose, but much lower than that achieved with deferiprone or deferox-amine in patients who have thalas-saemia, with mean daily iron excretion of 27 mg and 42 mg at doses of deferiprone of 75 mg/kg and 100 mg/kg, respectively.2Olivieri NF Koren G Hermann C et al.Comparison of iron chelator L1 and desferrioxamine in iron loaded patients.Lancet. 1990; 336: 1275-1279Summary PubMed Scopus (142) Google Scholar, 3Agarwal MB Gupte SS Viswanathan C et al.Long term assessment and safety of L1, an oral iron chelator, in transfusion dependent thalassaemia: Indian trial.BrJHaematol. 1992; 82: 460-466Crossref PubMed Scopus (168) Google Scholar The different pharmacokinetic profile of ICL670, including its slow rate of plasma clearance of half life of 12–16 h, limits the prospects of repeated administration and, consequently, its efficacy for iron removal.4Kontoghiorghes GJ Neocleous K Kolnagou A Benefits and risks of deferiprone in iron overload in thalassaemia and other conditions. Comparison of epidemiological and therapeutic aspects with deferoxamine.Drug Safety. 2003; 26: 553-584Crossref PubMed Scopus (97) Google Scholar The ferrokinetic profile of ICL670, which results mainly in an increase of faecal iron excretion, and its slow clearance from blood suggests accumulation of the drug, its metabolites, and iron complexes in lipid-soluble compartments of serum proteins and tissues and the inability of iron complexes to be cleared through the kidneys. Such properties increase the likelihood of toxic effects, similar to those of 8-hydroxyquinoline, which has similar lipophilicity to ICL670.5Yamamoto RS Williams GM Frankel HH Weisburger JH 8-Hydroxyquinoline: chronic toxicity and inhibitory effect on the carcinogenicity of N-2-fluorenylacetamide.Toxic Appl Pharmacol. 1971; 19: 687-698Crossref PubMed Scopus (50) Google Scholar Lipophilic chelators similar to ICL670, including 8-hydroxyquinoline, also cause an increase in the absorption of iron.4Kontoghiorghes GJ Neocleous K Kolnagou A Benefits and risks of deferiprone in iron overload in thalassaemia and other conditions. Comparison of epidemiological and therapeutic aspects with deferoxamine.Drug Safety. 2003; 26: 553-584Crossref PubMed Scopus (97) Google Scholar, 5Yamamoto RS Williams GM Frankel HH Weisburger JH 8-Hydroxyquinoline: chronic toxicity and inhibitory effect on the carcinogenicity of N-2-fluorenylacetamide.Toxic Appl Pharmacol. 1971; 19: 687-698Crossref PubMed Scopus (50) Google Scholar A major drawback in understanding the ferrokinetic and pharmacodynamic characteristics of ICL670 is the absence of information about the isolation and characterisation of the metabolite(s) of ICL670, some of which may have iron-chelating properties. These characteristics may explain several unexplained observations in relation to unsaturated iron binding capacity (UIBC) in serum, why the results for total exposure to the drug as estimated by the area under the curve (AUC) were not proportional to the ICL670 dose; and why plasma concentrations of the iron complex Fe-[ICL670]2 were not related to dose. Another concern about ICL670 is the cost to patients—only if it is cheaper than deferoxamine and deferiprone will it benefit most of the patients with thalassaemia in developing countries.4Kontoghiorghes GJ Neocleous K Kolnagou A Benefits and risks of deferiprone in iron overload in thalassaemia and other conditions. Comparison of epidemiological and therapeutic aspects with deferoxamine.Drug Safety. 2003; 26: 553-584Crossref PubMed Scopus (97) Google Scholar The introduction of new iron-chelating drugs may ultimately improve iron-chelation therapy for patients with thalassaemia and other disorders. As with deferiprone or deferoxamine, patients with thalassaemia are expected to have variable response with respect to ICL670. Protocols to select the most effective and least toxic drug, or drug combinations, for each patient may increase the therapeutic benefits for patients who do not respond to, or have toxic side-effects from, a single chelating drug.