General

Mechanism of Action/Pharmacodynamics

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.

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.

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 aged 18-65 years. No evidence of prolongation of the QTc interval was observed in this study.

Pharmacokinetics

Absorption

Exjade is absorbed following oral administration with median times to maximum plasma concentration (tmax) of about 1.5 to 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 to 2.3 after multiple doses. The absolute bioavailability (AUC) of deferasirox tablets for oral suspension is 70% compared to an intravenous dose.

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 ± 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%). No evidence for induction or inhibition of enzymes at therapeutic doses has been observed.

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 to 16 hours following oral administration.

Special Populations

Renal Insufficiency

Deferasirox is minimally (8%) excreted via the kidney. Exjade has not been studied in patients with renal impairment. (See PRECAUTIONS, Laboratory Tests, and ADVERSE REACTIONS.)

Hepatic Insufficiency

Deferasirox is principally excreted by glucuronidation and is minimally (8%) metabolized by oxidative cytochrome P450 enzymes. Exjade has not been studied in patients with hepatic impairment. Exjade treatment has been initiated in patients with baseline liver transaminase levels up to 5 times the upper limit of the normal range. The pharmacokinetics of deferasirox were not influenced by such transaminase levels.

Pediatric/Geriatric Patients

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. (See PRECAUTIONS, Pediatric Use.) 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.

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.

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