Deferiprone Other names: 3-hydroxy-1,2-dimethylpyridin-4-one

Deferiprone (3-hydroxy-1,2-dimethylpyridin-4-one) is a bidentate ligand which binds iron in a 3:1 molar ratio.

Pharmacodynamic effects

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. Data from the published literature on iron balance studies in patients with thalassaemia major show that the use of deferiprone concurrently with deferoxamine (coadministration of both chelators during the same day, either simultaneously or sequentially, e.g., deferiprone during the day and deferoxamine during the night), promotes greater iron excretion than either drug alone. Doses of deferiprone in those studies ranged from 50 to 100 mg/kg/day and doses of deferoxamine from 40 to 60 mg/kg/day. However, chelation therapy may not necessarily protect against iron-induced organ damage.

Absorption

Deferiprone is rapidly absorbed from the upper part of the gastrointestinal tract. Peak serum concentration occurs 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.

Renal impairment

An open-label, non-randomized, parallel group clinical study was conducted to evaluate the effect of impaired renal function on the safety, tolerability, and pharmacokinetics of a single 33 mg/kg oral dose of deferiprone. Subjects were categorized into 4 groups based on estimated glomerular filtration rate (eGFR): healthy volunteers (eGFR ≥90 mL/min/1.73m²), mild renal impairment (eGFR 60-89 mL/min/1.73m²), moderate renal impairment (eGFR 30–59 mL/min/1.73m²), and severe renal impairment (eGFR 15–29 mL/min/1.73m²). Systemic exposure to deferiprone and to its metabolite deferiprone 3-O-glucuronide was assessed by the PK parameters C_max and AUC.

Regardless of the degree of renal impairment, the majority of the dose of deferiprone was excreted in the urine over the first 24 hours as deferiprone 3-O-glucuronide. No significant effect of renal impairment was seen on systemic exposure to deferiprone. Systemic exposure to the inactive 3-O-glucuronide increased with decreasing eGFR. Based on the results of this study, no adjustment of the deferiprone dosage regimen is required in patients with impaired renal function. The safety and pharmacokinetics of deferiprone in patients with end stage renal disease is unknown.

Hepatic impairment

An open-label, non-randomized, parallel group clinical study was conducted to evaluate the effect of impaired hepatic function on the safety, tolerability, and pharmacokinetics of a single 33 mg/kg oral dose of deferiprone. Subjects were categorized into 3 groups based on the Child-Pugh classification score: healthy volunteers, mild hepatic impairment (Class A: 5–6 points), and moderate hepatic impairment (Class B: 7–9 points). Systemic exposure to deferiprone and to its metabolite deferiprone 3-O-glucuronide was assessed by the PK parameters C_max and AUC. Deferiprone AUCs did not differ between treatment groups, but C_max was decreased by 20% in mildly or moderately hepatically impaired subjects compared with healthy volunteers. Deferiprone-3-O-glucuronide AUC was decreased by 10% and C_max by 20% in mildly and moderately impaired subjects compared with healthy volunteers. A serious adverse event of acute liver and renal injury was seen in one subject with moderate hepatic impairment. Based on the results of this study, no adjustment of the deferiprone dosage regimen is required in patients with mildly or moderately impaired hepatic function.

The influence of severe hepatic impairment on the pharmacokinetics of deferiprone and deferiprone 3-O-glucuronide has not been evaluated. The safety and pharmacokinetics of deferiprone in patients with severe hepatic impairment is unknown.

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 animals.

Deferiprone was teratogenic and embryotoxic in reproductive studies in non-iron-loaded pregnant rats and rabbits at doses at least as low as 25 mg/kg/day. No effects on fertility or early embryonic development were noted in non-iron-loaded male and female rats that received deferiprone orally at doses of up to 75 mg/kg twice daily for 28 days (males) or 2 weeks (females) prior to mating and until termination (males) or through early gestation (females). In females, an effect on the oestrous cycle delayed time to confirmed mating at all doses tested.

No prenatal and postnatal reproductive studies have been conducted in animals.