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Pharmacotherapeutic Group: Iron Chelator. ATC Code: V03AC02.
Pharmacology: Pharmacodynamics: Tablet: Deferiprone is 3-hydroxy-1,2-dimethylpyridin-4-one, a bidentate ligand which binds to iron in a 3:1 molar ratio.
Clinical studies have demonstrated that deferiprone is effective in promoting iron excretion and that a dose of 25 mg/kg 3 times daily can prevent the progression of iron accumulation as assessed by serum ferritin in patients with transfusion-dependent thalassemia. However, chelation therapy may not necessarily protect against iron-induced organ damage.
Oral Solution: No clinical studies were performed to assess the relationship between the dose of FERRIPROX and the amount of iron eliminated from the body.
Cardiac Electrophysiology: At a dose 1.5 times the maximum recommended dose, FERRIPROX does not prolong the QT interval to any clinically relevant extent.
Mechanism of Action: Deferiprone is a chelating agent with an affinity for ferric ion (iron III). Deferiprone binds with ferric ions to form neutral 3:1 (deferiprone:iron) complexes that are stable over a wide range of pH values. Deferiprone has a lower binding affinity for other metals such as copper, aluminum and zinc than for iron.
Pharmacokinetics: Tablet: Absorption: Deferiprone is rapidly absorbed from the upper part of the gastrointestinal tract. Peak serum concentration is reported to occur 45-60 min following a single dose in fasted patients. This may be extended to 2 hrs in fed patients.
Following a dose of 25 mg/kg, lower peak serum concentrations have been detected in patients in the fed state (85 micromol/L) than in the fasting state (126 micromol/L), although there was no decrease in the amount of deferiprone absorbed when it was given with food.
Biotransformation: Deferiprone is metabolized predominantly to a glucuronide conjugate. This metabolite lacks iron-binding capability due to inactivation of the 3-hydroxy group of deferiprone. Peak serum concentrations of glucuronide occur 2-3 hrs after administration of deferiprone.
Elimination: In humans, deferiprone is eliminated mainly via the kidneys; 75-90% of the ingested dose is reported to be recovered in the urine in the first 24 hrs, in the form of the free deferiprone, the glucuronide metabolite and the iron-deferiprone complex. A variable amount of elimination via the feces has been reported. The elimination half-life in most patients is 2-3 hrs.
Oral Solution: Deferiprone is rapidly absorbed from the upper part of the gastrointestinal tract, appearing in the blood within 5 to 10 minutes of oral administration. Peak serum concentrations occur approximately 1 hour after a single dose in fasted healthy subjects and patients, and up to 2 hours after a single dose in the fed state. Administration with food decreased the maximum concentration (Cmax) of deferiprone by 38% and the area under the concentration-time curve (AUC) by 10%. The magnitude of the exposure change does not warrant dose adjustment.
In healthy subjects, the mean Cmax of deferiprone in serum was about 20 mcg/mL, and the mean AUC was about 50 mcg∙h/mL following oral administration of a 1,500 mg dose of FERRIPROX tablets or oral solution in the fasting state. Dose proportionality over the labeled dosage range of 25 to 33 mg/kg three times per day (75 to 99 mg/kg per day) has not been studied.
The elimination half-life of deferiprone is approximately 2 hours. Following oral administration, 75% to 90% of the administered dose is recovered in the urine in the first 24 hours, primarily as metabolite. In humans, the majority of the deferiprone is metabolized, primarily by UGT1A6. The contribution of extrahepatic (e.g., renal) UGT1A6 is unknown. The major metabolite of deferiprone is the 3-O-glucuronide, which lacks iron binding capability.
In a bioequivalence study, the rate (Cmax) and the extent (AUC) of drug absorption of the solution and tablet formulations were shown to be equivalent.
Specific Populations: The pharmacokinetics of deferiprone has not been studied in geriatric or pediatric populations, and the influence of race, gender, or obesity has not been established.
Drug Interactions: Deferiprone is primarily eliminated via metabolism to the 3-O-glucuronide. In vitro UGT1A6 is primarily responsible for the glucuronidation of deferiprone which can be reduced up to 78% in the presence of the UGT1A6 inhibitor phenylbutazone.
Toxicology: Tablet: Preclinical Safety Data: Preclinical studies have been conducted in animal species including mice, rats, rabbits, dogs and monkeys. The most common findings in non-iron-loaded animals at doses of ≥100 mg/kg/day were hematologic effects eg, bone marrow hypocellularity, and decreased WBC, RBC and/or platelet counts in peripheral blood.
Atrophy of the thymus, lymphoid tissues and testis, and hypertrophy of the adrenals, were reported at doses of ≥100 mg/kg/day in non-iron-loaded animals.
No carcinogenicity studies in animals have been conducted with deferiprone. The genotoxic potential of deferiprone was evaluated in a set of in vivo tests. Deferiprone did not show direct mutagenic properties; however, it did display clastogenic characteristics in vivo in animals.
Deferiprone was teratogenic and embryotoxic in reproductive studies in non-iron-loaded rats and rabbits at doses at least as low as 25 mg/kg/day. No prenatal and postnatal reproductive studies have been conducted in animals.
Oral Solution: Clinical Studies: In a prospective, planned, pooled analysis of patients from several studies, the efficacy of FERRIPROX was assessed in transfusion-dependent iron overload patients in whom previous iron chelation therapy had failed or was considered inadequate due to poor tolerance. The main criterion for chelation failure was serum ferritin > 2,500 mcg/L before treatment with FERRIPROX. FERRIPROX therapy (35-99 mg/kg/day) was considered successful in individual patients who experienced a ≥ 20% decline in serum ferritin within one year of starting therapy.
Data from a total of 236 patients were analyzed. Of the 224 patients with thalassemia who received deferiprone monotherapy and were eligible for serum ferritin analysis, 105 (47%) were male and 119 (53%) were female. The mean age of these patients was 18.2 years.
For the patients in the analysis, the endpoint of at least a 20% reduction in serum ferritin was met in 50% (of 236 subjects), with a 95% confidence interval of 43% to 57%.
A small number of patients with thalassemia and iron overload were assessed by measuring the change in the number of milliseconds (ms) in the cardiac MRI T2* value before and after treatment with deferiprone for one year. There was an increase in cardiac MRI T2* from a mean at baseline of 11.8±4.9 ms to a mean of 15.1±7.0 ms after approximately one year of treatment. The clinical significance of this observation is not known.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies have not been conducted with deferiprone. However, in view of the genotoxicity results, and the findings of mammary gland hyperplasia and mammary gland tumors in rats treated with deferiprone in the 52-week toxicology study, tumor formation in carcinogenicity studies must be regarded as likely.
Deferiprone was positive in a mouse lymphoma cell assay in vitro. Deferiprone was clastogenic in an in vitro chromosomal aberration test in mice and in a chromosomal aberration test in Chinese Hamster Ovary cells. Deferiprone given orally or intraperitoneally was clastogenic in a bone marrow micronucleus assay in non-iron-loaded mice. A micronucleus test was also positive when mice predosed with iron dextran were treated with deferiprone. Deferiprone was not mutagenic in the Ames bacterial reverse mutation test.
A fertility and early embryonic development study of deferiprone was conducted in rats. Sperm counts, motility and morphology were unaffected by treatment with deferiprone. There were no effects observed on male or female fertility or reproductive function at the highest dose which was 25% of the MRHD based on body surface area.
