Pharmacology: Pharmacodynamics: Mechanism of action: 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.
Dose/concentration/time-pharmacodynamic response relationship: Data is not available.
Mechanism of toxicity: Data is not available.
Pharmacokinetics: Absorption: Deferasirox is absorbed following oral administration with median times to maximum plasma concentration (Tmax) of approximately 1.5-4 hours. The absolute bioavailability of deferasirox tablets for oral suspension is 70% compared with an intravenous dose. The bioavailability of deferasirox is variably increased when taken with a meal.
Distribution: Deferasirox is highly protein bound (approximately 99%), almost exclusively to serum albumin. The volume of distribution at steady state 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 UDP-glucuronosyltransferase 1A1 (UGT1A1) and to a lesser extent UGT1A3. Cytochrome P450 (CYP-450)-catalyzed (oxidative) metabolism of deferasirox appears to be minor in humans (approximately 8%).
Elimination: Deferasirox and metabolites are primarily excreted in the feces (84% of the dose). Renal excretion of deferasirox and metabolites is minimal (8% of the administered dose). The mean terminal half-life ranged from 8-16 hours following oral administration.
Linearity/non-linearity pharmacokinetics: The maximum plasma concentration (Cmax) and area under the curve (AUC) of deferasirox increase approximately linearly with the dose after single administration and under steady-state conditions. Exposure to deferasirox increased by an accumulation factor of 1.3-2.3 after multiple doses.
Special populations: Hepatic function impairment: Deferasirox exposure in patients with varying degrees of hepatic impairment was increased compared with patients with normal hepatic function. The average total (free and bound) AUC of deferasirox increased 16% in mild (Child-Pugh class A) hepatic impairment and 76% in moderate (Child-Pugh class B) hepatic impairment compared with normal hepatic function.
Pediatric: Following oral administration of single or multiple doses, systemic exposure of adolescents and children to deferasirox is less than in adults. In children younger than 6 years of age, systemic exposure is approximately 50% lower than in adults.
Gender: Women have a moderately lower apparent clearance (by 17.5%) of deferasirox compared with men.