Deferiprone

Abstract

Patients with β-thalassaemia and other transfusion-dependent diseases develop iron overload from chronic blood transfusions and require regular iron chelation to prevent potentially fatal iron-related complications. The only iron chelator currently widely available is deferoxamine, which is expensive and requires prolonged subcutaneous infusion 3 to 7 times per week or daily intramuscular injections. Moreover, some patients are unable to tolerate deferoxamine and compliance with the drug is poor in many patients. Deferiprone is the most extensively studied oral iron chelator to date. Non-comparative clinical studies mostly in patients with β-thalassaemia have demonstrated that deferiprone 75 to 100 mg/kg/day can reduce iron burden in regularly transfused iron-overloaded patients. Serum ferritin levels are generally reduced in patients with very high pretreatment levels and are frequently maintained within an acceptable range in those who are already adequately chelated. Deferiprone is not effective in all patients (some of whom show increases in serum ferritin and/or liver iron content, particularly during long term therapy). This may reflect factors such as suboptimal dosage and/or severe degree of iron overload at baseline in some instances. Although few long term comparative data are available, deferiprone at the recommended dosage of 75 mg/kg/day appears to be less effective than deferoxamine; however, compliance is superior with deferiprone, which may partly compensate for this. Deferiprone has additive, or possibly synergistic, effects on iron excretion when combined with deferoxamine. The optimum dosage and long term efficacy of deferiprone, and its effects on survival and progression of iron-related organ damage, remain to be established. The most important adverse effects in deferiprone-treated patients are arthropathy and neutropenia/agranulocytosis. Other adverse events include gastrointestinal disturbances, ALT elevation, development of antinuclear antibodies and zinc deficiency. With deferiprone, adverse effects occur mostly in heavily iron-loaded patients, whereas with deferoxamine adverse effects occur predominantly when body iron burden is lower. Conclusion: Deferiprone is the most promising oral iron chelator under development at present. Further studies are required to determine the best way to use this new drug. Although it appears to be less effective than deferoxamine at the recommended dosage and there are concerns regarding its tolerability, it may nevertheless offer a therapeutic alternative in the management of patients unable or unwilling to receive the latter drug. Deferiprone also shows promise as an adjunct to deferoxamine therapy in patients with insufficient response and may prove useful as a maintenance treatment to interpose between treatments. Deferiprone is an oral bidentate iron chelator which binds to iron in a 3: 1 ratio. It also binds other metals including aluminium, gallium, copper and zinc, but not calcium or magnesium. Deferiprone reduces body iron content in iron-overloaded animals and humans. Iron excretion is related to dosage and the degree of iron overload, and occurs largely by the renal route. Deferiprone appears to mobilise iron from both reticuloendothelial and hepatocellular pools, from transferrin, ferritin and haemosiderin and from pathological iron deposits in intact red blood cells from patients with thalassaemia or sickle-cell anaemia. Depending on concentration, deferiprone has been reported to promote (at low concentrations, in vitro), and conversely to protect against (at high concentrations), oxidative damage caused by oxygen free radicals. As with deferoxamine, deferiprone inhibits proliferation of several cell lines in vitro and may induce apoptosis. It has also shown myelosuppressive effects in animals and humans. Although in vitro data suggest that deferiprone is markedly less toxic than deferoxamine to bone marrow myeloid progenitors, the clinical relevance of this is unclear, as deferiprone-induced myelosuppression may occur via a reactive metabolite-induced event mediated by the immune system. Peak plasma concentrations (C_max) are reached within approximately 1 hour after oral administration of deferiprone. Food intake reduces the rate, but not the extent, of absorption of the drug. Administration of deferiprone 75 mg/kg/day at 12-hourly intervals produced a C_max of 34.6 mg/L and area under the plasma concentration-time curve (AUC) of 137.5 mg/L · h in patients with β-thalassaemia. Coadministration of iron (ferrous sulfate 600mg) reduced the AUC by about 20% in healthy volunteers. It is not clear whether deferiprone induces its own metabolism in vivo. This has been demonstrated in vitro. Trough plasma concentrations of deferiprone decreased during long term treatment with the drug in 1 study, but this was not corroborated by other studies. The volume of distribution after administration of deferiprone 75 mg/kg/day was 1.55 or 1.73 L/kg at steady state (depending on the dosage schedule) in patients with β-thalassaemia. Deferiprone was found to accumulate (≈3-fold) in thalassaemic, but not normal or sickle, red blood cells in vitro. Deferiprone is metabolised predominantly (>85%) to a glucuronide conjugate that lacks chelating properties. The drug, its conjugate and the deferiprone-iron complex are mainly excreted by the kidney and approximately 80% of a dose is recovered in the urine. Deferiprone is rapidly eliminated, with an elimination half-life (t½β) of approximately 1 to 2.5 hours in patients with β-thalassaemia. The t½β of deferiprone glucuronide was significantly correlated with creatinine clearance and this metabolite was found to accumulate in a patient with renal dysfunction. Although deferiprone is metabolised by the liver, the effects of hepatic impairment on the...