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Mechanism of Action

Exjade (deferasirox) is an orally active chelator that is selective for iron (as Fe3+). It is a tridentate ligand that binds iron with high affinity in a 2:1 ratio. Although deferasirox has very low affinity for zinc and copper there are variable decreases in the serum concentration of these trace metals after the administration of deferasirox. The clinical significance of these decreases is uncertain.

Pharmacodynamics

Pharmacodynamic effects tested in an iron balance metabolic study showed that deferasirox (10, 20 and 40 mg/kg per day) was able to induce a mean net iron excretion (0.119, 0.329 and 0.445 mg Fe/kg body weight per day, respectively) within the clinically relevant range (0.1-0.5 mg/kg per day). Iron excretion was predominantly fecal.

Pharmacokinetics

Absorption

Exjade is absorbed following oral administration with median times to maximum plasma concentration (tmax) of about 1.5-4 hours. The Cmax and AUC of deferasirox increase approximately linearly with dose after both single administration and under steady-state conditions. Exposure to deferasirox increased by an accumulation factor of 1.3-2.3 after multiple doses. The absolute bioavailability (AUC) of deferasirox tablets for oral suspension is 70% compared to an intravenous dose. The bioavailability (AUC) of deferasirox was variably increased when taken with a meal.

Distribution

Deferasirox is highly (~99%) protein bound almost exclusively to serum albumin. The percentage of deferasirox confined to the blood cells was 5% in humans. The volume of distribution at steady state (Vss) of deferasirox is 14.37 RMG 2.69 L in adults.

Metabolism

Glucuronidation is the main metabolic pathway for deferasirox, with subsequent biliary excretion. Deconjugation of glucuronidates in the intestine and subsequent reabsorption (enterohepatic recycling) is likely to occur. Deferasirox is mainly glucuronidated by UGT1A1 and to a lesser extent UGT1A3. CYP450-catalyzed (oxidative) metabolism of deferasirox appears to be minor in humans (about 8%). Deconjugation of glucuronide metabolites in the intestine and subsequent reabsorption (enterohepatic recycling) was confirmed in a healthy volunteer study in which the administration of cholestyramine 12 g twice daily (strongly binds to deferasirox and its conjugates) 4 and 10 hours after a single dose of deferasirox resulted in a 45% decrease in deferasirox exposure (AUC) by interfering with the enterohepatic recycling of deferasirox.

Excretion

Deferasirox and metabolites are primarily (84% of the dose) excreted in the feces. Renal excretion of deferasirox and metabolites is minimal (8% of the administered dose). The mean elimination half-life (t½) ranged from 8-16 hours following oral administration.

Pharmacokinetics in Special Populations

Pediatric: Following oral administration of single or multiple doses, systemic exposure of adolescents and children to deferasirox was less than in adult patients. In children < 6 years of age, systemic exposure was about 50% lower than in adults.

Geriatric: The pharmacokinetics of deferasirox have not been studied in geriatric patients (65 years of age or older).

Gender: Females have a moderately lower apparent clearance (by 17.5%) for deferasirox compared to males.

QT Prolongation

The effect of 20 and 40 mg/kg per day of deferasirox on the QT interval was evaluated in a single-dose, double-blind, randomized, placebo- and active-controlled (moxifloxacin 400 mg), parallel group study in 182 healthy male and female volunteers age 18-65 years. No evidence of prolongation of the QTc interval was observed in this study.

Clinical Studies

The primary efficacy study, Study 1, was a multicenter, open-label, randomized, active comparator control study to compare Exjade (deferasirox) and deferoxamine in patients with β-thalassemia and transfusional hemosiderosis. Patients ≥ 2 years of age were randomized in a 1:1 ratio to receive either oral Exjade at starting doses of 5, 10, 20 or 30 mg/kg once daily or subcutaneous Desferal (deferoxamine) at starting doses of 20 to 60 mg/kg for at least 5 days per week based on LIC (liver iron concentration) at baseline (2-3, > 3-7, > 7-14 and > 14 mg Fe/g dry weight). Patients randomized to deferoxamine who had LIC values < 7 mg Fe/g dry weight were permitted to continue on their prior deferoxamine dose, even though the dose may have been higher than specified in the protocol.

Patients were to have a liver biopsy at baseline and end of study (after 12 months) for LIC. The primary efficacy endpoint was defined as a reduction in LIC of ≥ 3 mg Fe/g dry weight for baseline values ≥ 10 mg Fe/g dry weight, reduction of baseline values between 7 and < 10 to < 7 mg Fe/g dry weight, or maintenance or reduction for baseline values < 7 mg Fe/g dry weight.

A total of 586 patients were randomized and treated, 296 with Exjade and 290 with deferoxamine. The mean age was 17.1 years (range, 2-53 years); 52% were females and 88% were Caucasian. The primary efficacy population consisted of 553 patients (Exjade n=276; deferoxamine n=277) who had LIC evaluated at baseline and 12 months or discontinued due to an adverse event. The percentage of patients achieving the primary endpoint was 52.9% for Exjade and 66.4% for deferoxamine. The relative efficacy of Exjade to deferoxamine cannot be determined from this study.

In patients who had an LIC at baseline and at end of study, the mean change in LIC was -2.4 mg Fe/g dry weight in patients treated with Exjade and -2.9 mg Fe/g dry weight in patients treated with deferoxamine.

Reduction of LIC and serum ferritin was observed with Exjade doses of 20 to 30 mg/kg per day. Exjade doses below 20 mg/kg per day failed to provide consistent lowering of LIC and serum ferritin levels (Figure 1). Therefore, a starting dose of 20 mg/kg per day is recommended [see DOSAGE AND ADMINISTRATION].

Figure 1: Changes in Liver Iron Concentration and Serum Ferritin Following EXJADE (5-30 mg/kg per day) in Study 1

Study 2 was an open-label, noncomparative trial of efficacy and safety of Exjade given for 1 year to patients with chronic anemias and transfusional hemosiderosis. Similar to Study 1, patients received 5, 10, 20, or 30 mg/kg per day of Exjade based on baseline LIC.

A total of 184 patients were treated in this study: 85 patients with β-thalassemia and 99 patients with other congenital or acquired anemias (myelodysplastic syndromes, n=47; Diamond-Blackfan syndrome, n=30; other, n=22). 19% of patients were < 16 years of age and 16% were ≥ 65 years of age. There was a reduction in the absolute LIC from baseline to end of study (-4.2 mg Fe/g dry weight).

Study 3 was a multicenter, open-label, randomized trial of the safety and efficacy of Exjade relative to deferoxamine given for 1 year in patients with sickle cell disease and transfusional hemosiderosis. Patients were randomized to Exjade at doses of 5, 10, 20, or 30 mg/kg per day or subcutaneous deferoxamine at doses of 20-60 mg/kg per day for 5 days per week according to baseline LIC.

A total of 195 patients were treated in this study: 132 with Exjade and 63 with deferoxamine. 44% of patients were < 16 years of age and 91% were Black. At end of study, the mean change in LIC (as measured by magnetic susceptometry by a superconducting quantum interference device) in the per protocol-1 (PP-1) population, which consisted of patients who had at least one postbaseline LIC assessment, was -1.3 mg Fe/g dry weight for patients receiving Exjade (n=113) and -0.7 mg Fe/g dry weight for patients receiving deferoxamine (n=54).

Last reviewed on RxList: 8/19/2011
This monograph has been modified to include the generic and brand name in many instances.