Chemical formula: C₂₁H₁₅N₃O₄ Molecular mass: 373.362 g/mol PubChem compound: 5493381
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.
In an iron-balance metabolic study 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.
Deferasirox 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 Cmax was increased by 30% (90% CI: 20.3% - 40.0%); however a clinical exposure/response analysis revealed no evidence of clinically relevant effects of such an increase.
Deferasirox granules demonstrate higher bioavailability compared to the deferasirox dispersible tablet formulation. After adjustment of the strength, the granules formulation (4 × 90 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 Cmax was increased by 34% (90% CI: 27.9% - 40.3%); however a clinical exposure/response analysis revealed no evidence of clinically relevant effects of such an increase.
Deferasirox (dispersible tablet formulation) is absorbed following oral administration with a median time to maximum plasma concentration (tmax) 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.
A food-effect study involving administration of the film-coated tablets to healthy volunteers 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 Cmax were slightly decreased after a low-fat meal (by 11% and 16%, respectively). After a high-fat meal, AUC and Cmax were increased (by 18% and 29%, respectively). The increases in Cmax 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.
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 glucuronidates in the intestine and subsequent reabsorption (enterohepatic recycling) is likely to occur: in a healthy volunteer study, 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 in vitro.
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 (t1/2) ranged from 8 to 16 hours. The transporters MRP2 and MXR (BCRP) are involved in the biliary excretion of deferasirox.
The Cmax and AUC0-24h 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.
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.
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.
The pharmacokinetics of deferasirox have not been studied in elderly patients (aged 65 or older).
The pharmacokinetics of deferasirox have not been studied 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.
In a clinical study using single doses of 20 mg/kg deferasirox dispersible tablets, the average exposure was increased by 16% in subjects with mild hepatic impairment (Child-Pugh Class A) and by 76% in subjects with moderate hepatic impairment (Child-Pugh Class B) compared to subjects with normal hepatic function. The average Cmax of deferasirox in subjects with mild or moderate hepatic impairment was increased by 22%. Exposure was increased 2.8-fold in one subject with severe hepatic impairment (Child-Pugh Class C).
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity or carcinogenic potential. The main findings were kidney toxicity and lens opacity (cataracts). Similar findings were observed in neonatal and juvenile animals. The kidney toxicity is considered mainly due to iron deprivation in animals that were not previously overloaded with iron.
Tests of genotoxicity in vitro were negative (Ames test, chromosomal aberration test) while deferasirox caused formation of micronuclei in vivo in the bone marrow, but not liver, of non-iron-loaded rats at lethal doses. No such effects were observed in iron-preloaded rats. Deferasirox was not carcinogenic when administered to rats in a 2-year study and transgenic p53+/- heterozygous mice in a 6-month study.
The potential for toxicity to reproduction was assessed in rats and rabbits. Deferasirox was not teratogenic, but caused increased frequency of skeletal variations and stillborn pups in rats at high doses that were severely toxic to the non-iron-overloaded mother. Deferasirox did not cause other effects on fertility or reproduction.
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