, Volume 67, Issue 15, pp 2211-2230
Date: 14 Sep 2012

Deferasirox

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Abstract

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 β-thalassaemia major aged ≥6 years and, in the US, in all transfusional chronic iron overload patients aged ≥2 years. Deferasirox is highly selective for iron as Fe3+.

In ≈1-year clinical trials of patients with transfusional chronic iron overload associated with β-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.

Pharmacological Properties

Deferasirox is a tridentate iron chelator with high affinity for iron as Fe3+; two molecules of deferasirox bind to one Fe3+. In clinical trials, most (≈70%) patients with transfusional chronic iron overload treated with deferasirox 20 or 30 mg/kg/ day (the approved regimen) achieved net iron excretion or maintained iron balance. Preliminary data indicate that after treatment with deferasirox for ≈1 year, patients with transfusional chronic iron overload demonstrated an improvement in myocadial iron load and labile plasma iron.

The deferasirox maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUC) were dose dependent, although time to reach Cmax was independent of dose (1–2 hours). Time to steady state is 3 days, and at steady state, AUC was increased by an accumulation factor of 1.3–2.3. Deferasirox is mainly metabolised by hepatic glucuronidation and is excreted in bile. The mean elimination half-life of deferasirox is 7.2–18.5 hours and, although variable between study patients, permits once-daily administration. Deferasirox is predominantly excreted through the faecal route (83%), mostly as the unchanged drug. Renal excretion accounts for 6–8% of an administered dose. At therapeutic dosages, deferasirox did not induce or inhibit cytochrome P450 enzymes.

Therapeutic Efficacy

The iron chelation efficacy of deferasirox was investigated in five trials of ≈1 year’s duration in paediatric and adult patients, including a phase III noninferi-oritytrial. The underlying anaemic condition in study patients was predominantly β-thalassaemia major; other conditions included sickle cell disease, myelodysplastic syndrome, and Diamond-Blackfan and other rare anaemias.

In the phase III β-thalassaemia trial, dosages of deferasirox or deferoxamine were assigned according to baseline LIC. Although noninferiority to deferoxamine was not established in the overall study population, deferasirox was noninferior to deferoxamine in a predefined subgroup analysis of patients with higher baseline LIC (≥7mg Fe/g dry weight) who were treated with 20 or 30 mg/ kg/day. In addition, LIC was significantly reduced from baseline in this group of patients; reductions in serum ferritin levels were also observed, although no statistical analyses were reported. Limited efficacy data for deferasirox are available in the treatment of patients with sickle cell disease, myelodysplastic syndrome or other chronic rare anaemias; similar changes in LIC and serum ferritin levels to those seen in patients with β-thalassaemia were observed in patients with these conditions.

Preliminary data indicate that a larger number of patients indicated satisfaction, convenience and less time lost to treatment with deferasirox than deferox-amine. These data suggest that treatment with deferasirox may be beneficial in patients with a history of noncompliance to infusional deferoxamine.

Cost-utility analyses from a US or UK perspective in patients with β-thalassaemia, sickle cell disease or myelodysplastic syndrome suggest that deferasirox is a cost-effective treatment relative to branded or generic deferoxamine. Incremental quality-adjusted life years gained from treatment of patients with β-thalassaemia major with deferasirox relative to deferoxamine were mainly attributed to patient preference for an oral iron chelator.

Tolerability

Deferasirox was associated with a clinically manageable tolerability profile. The most common adverse events associated with deferasirox treatment included transient gastrointestinal adverse events (nausea, vomiting, abdominal pain, constipation and diarrhoea) and skin rash. Other adverse events include elevated serum creatinine, and less frequently, elevated ALT levels and visual and auditory disturbances; regular monitoring and careful management are recommended. Postmarketing cases of renal failure and cytopenia have been reported.