Ferasiro Mechanism of Action

Pharmacotherapeutic group: Iron chelating agents. ATC code: V03AC03.
Pharmacology: Pharmacodynamics: Mechanism of action: Deferasirox is an orally active chelator that is highly selective for iron (III). It is a tridentate ligand that binds iron with high affinity in a 2:1 ratio. Deferasirox promotes excretion of iron, primarily in the faeces. Deferasirox has low affinity for zinc and copper, and does not cause constant low serum levels of these metals.
Pharmacodynamic effects: In iron-overloaded adult thalassaemic patients, deferasirox at daily doses of 10, 20 and 40 mg/kg (dispersible tablet formulation) induced the mean net excretion of 0.119, 0.329 and 0.445 mg Fe/kg body weight/day, respectively.
Pharmacokinetics: FERASIRO film-coated tablets demonstrate higher bioavailability compared to the Deferasirox dispersible tablet formulation. After adjustment of the strength, the film-coated tablet formulation (360 mg strength) was equivalent to Deferasirox dispersible tablets (500 mg strength) with respect to the mean area under the plasma concentration time curve (AUC) under fasting conditions. The C_max was increased; however a clinical exposure/response analysis revealed no evidence of clinically relevant effects of such an increase.
Absorption: Deferasirox (dispersible tablet formulation) is absorbed following oral administration with a median time to maximum plasma concentration (t_max) of about 1.5 to 4 hours. The absolute bioavailability (AUC) of deferasirox (dispersible tablet formulation) is about 70% compared to an intravenous dose. The absolute bioavailability of the film-coated tablet formulation has not been determined. Bioavailability of deferasirox film-coated tablets was 36% greater than that with dispersible tablets.
An administration of the film-coated tablets to healthy patients under fasting conditions and with a low-fat (fat content <10% of calories) or high-fat (fat content >50% of calories) meal indicated that the AUC and C_max were slightly decreased after a low-fat meal (by 11% and 16%, respectively). After a high-fat meal, AUC and C_max were increased (by 18% and 29%, respectively). The increases in C_max due to the change in formulation and due to the effect of a high-fat meal may be additive and therefore, it is recommended that the film-coated tablets should be taken either on an empty stomach or with a light meal.
Distribution: Deferasirox is highly (99%) protein bound to plasma proteins, almost exclusively serum albumin, and has a small volume of distribution of approximately 14 litres in adults.
Biotransformation: Glucuronidation is the main metabolic pathway for deferasirox, with subsequent biliary excretion. Deconjugation of glucuronides in the intestine and subsequent reabsorption (enterohepatic recycling) is likely to occur: the administration of cholestyramine after a single dose of deferasirox resulted in a 45% decrease in deferasirox exposure (AUC). Deferasirox is mainly glucuronidated by UGT1A1 and to a lesser extent UGT1A3. CYP450-catalysed (oxidative) metabolism of deferasirox appears to be minor in humans (about 8%). No inhibition of deferasirox metabolism by hydroxyurea was observed.
Elimination: Deferasirox and its metabolites are primarily excreted in the faeces (84% of the dose). Renal excretion of deferasirox and its metabolites is minimal (8% of the dose). The mean elimination half-life (t_½) ranged from 8 to 16 hours. The transporters MRP2 and MXR (BCRP) are involved in the biliary excretion of deferasirox.
Linearity/non-linearity: The C_max and AUC_0-24h of deferasirox increase approximately linearly with dose under steady-state conditions. Upon multiple dosing exposure increased by an accumulation factor of 1.3 to 2.3.
Characteristics in patients: Paediatric patients: The overall exposure of adolescents (12 to ≤17 years) and children (2 to <12 years) to deferasirox after single and multiple doses was lower than that in adult patients. In children younger than 6 years old exposure was about 50% lower than in adults. Since dosing is individually adjusted according to response this is not expected to have clinical consequences.
Gender: Females have a moderately lower apparent clearance (by 17.5%) for deferasirox compared to males. Since dosing is individually adjusted according to response this is not expected to have clinical consequences.
Elderly patients: There is no pharmacokinetics data on use of deferasirox in elderly patients (aged 65 or older).
Renal or hepatic impairment: There is no pharmacokinetics data on use of deferasirox in patients with renal impairment. The pharmacokinetics of deferasirox were not influenced by liver transaminase levels up to 5 times the upper limit of the normal range.
Using single doses of 20 mg/kg deferasirox dispersible tablets, the average exposure was increased by 16% in patients with mild hepatic impairment (Child-Pugh Class A) and by 76% in patients with moderate hepatic impairment (Child-Pugh Class B) compared to patients with normal hepatic function. The average C_max of deferasirox in patients with mild or moderate hepatic impairment was increased by 22%. Exposure was increased 2.8-fold in one patient with severe hepatic impairment (Child-Pugh Class C) (see Dosage & Administration and Precautions).