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Pharmacotherapeutic Group: Iron chelating agents. ATC Code: V03AC02.
Pharmacology: Pharmacodynamics: The active substance is deferiprone (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 three times per day can prevent the progression of iron accumulation as assessed by serum ferritin, in patients with transfusion-dependent thalassaemia. However, chelation therapy may not necessarily protect against iron-induced organ damage.
Deferiprone has been investigated in 247 patients in two phase III trials and a compassionate use programme. Serum ferritin was chosen as the primary efficacy criterion in the studies. In one study of two‐year duration deferiprone was compared to deferoxamine. The mean serum ferritin levels were not significantly different in the two treatment groups, but mean hepatic iron concentration in deferiprone treated patients seems to increase more than in deferoxamine treated patients. Therefore deferiprone at the recommended dose could be less effective than deferoxamine.
The other study was a supportive open, non-comparative study. In this study patients maintained serum ferritin values at pre-study levels. The primary end-point was the incidence of agranulocytosis, which occurred at a frequency of 1.2%.
Pharmacokinetics: FC tab: Deferiprone is rapidly absorbed from the upper part of the gastro-intestinal tract. Peak serum concentration is reported to occur 45 to 60 minutes following a single dose in fasted patients. This may be extended to 2 hours in fed patients. Deferiprone is metabolised predominantly to a glucuronide conjugate. This metabolite lacks ironbinding capacity due to inactivation of the 3-hydroxy group of deferiprone. In humans, deferiprone is eliminated mainly via the kidneys with reports of 75% to 90% of the ingested dose being recovered in the urine in the first 24 hours, in the form of free deferiprone, the glucuronide metabolite and the iron-deferiprone complex.
Oral soln: Absorption: Deferiprone is rapidly absorbed from the upper part of the gastrointestinal tract. Peak serum concentration is reported to occur 45 to 60 minutes following a single dose in fasted patients. This may be extended to 2 hours in fed patients.
Following a dose of 25 mg/kg, lower peak serum concentrations have been detected in patients in the fed state (85 µmol/l) than in the fasting state (126 µmol/l), although there was no decrease in the amount of deferiprone absorbed when it was given with food.
Biotransformation: Deferiprone is metabolised 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 the glucuronide occur 2 to 3 hours after administration of deferiprone.
Elimination: In humans, deferiprone is eliminated mainly via the kidneys; 75% to 90% of the ingested dose is reported as being recovered in the urine in the first 24 hours, in the form of free deferiprone, the glucuronide metabolite and the iron‐deferiprone complex. A variable amount of elimination via the faeces has been reported. The elimination half‐life in most patients is 2 to 3 hours.
Toxicology: Preclinical safety data: Non-clinical 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 and above were hematologic effects such as 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 or greater 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 vitro and in vivo tests. Deferiprone did not show direct mutagenic properties; however, it did display clastogenic characteristics in in vitro assays and 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.
