Deferoxamine Other names: Desferoxamine B Desferrioxamine DFOA DFB Desferrioxamine B Desferal DFO-B

Deferoxamine is a chelating agent for trivalent iron and aluminium ions; the resulting chelates (ferrioxamine and aluminoxamine) are stable and non-toxic. Neither chelate undergoes intestinal absorption, and any formed systemically as a result of parenteral administration is rapidly excreted via the kidneys without deleterious effects. Deferoxamine takes up iron either free or bound to ferritin and haemosiderin. Similarly it mobilises and chelates tissue bound aluminium. It does not remove iron from haemin containing substances including haemoglobin and transferrin. Since both ferrioxamine and aluminoxamine are completely excreted, deferoxamine promotes the excretion of iron and aluminium in urine and faeces, thus reducing pathological iron or aluminium deposits in the organs and tissues.

Absorption

Deferoxamine is rapidly absorbed after intramuscular bolus injection or slow subcutaneous infusion, but only poorly absorbed from the gastrointestinal tract in the presence of intact mucosa.

During peritoneal dialysis desferrioxamine is absorbed if administered in the dialysis fluid.

Distribution

In healthy volunteers peak plasma concentrations of desferrioxamine (15.5 micro mol/L (87 micro g/mL)) were measured 30 minutes after an intramuscular injection of 10 mg/kg desferrioxamine. One hour after injection the peak concentration of ferrioxamine was 3.7 micro mol/L (2.3 micro g/mL). Less than 10% of desferrioxamine is bound to serum proteins in vitro.

Biotransformation

Four metabolites of desferrioxamine were isolated from urine of patients with iron overload. The following biotransformation reactions were found to occur with desferrioxamine: transamination and oxidation yielding an acid metabolite, beta-oxidation also yielding an acid metabolite, decarboxylation and N-hydroxylation yielding neutral metabolites.

Elimination

Both desferrioxamine and ferrioxamine a biphasic elimination after intramuscular injection in healthy volunteers; for desferrioxamine the apparent distribution half-life is 1 hour, and for ferrioxamine 2.4 hours. The apparent terminal half-life is 6 hours for both. Within six hours of injection, 22% of the dose appears in the urine as desferrioxamine and 1% as ferrioxamine.

Characteristics in patients

In patients with haemochromatosis peak plasma levels of 7.0 micro mol/L (3.9 micro g/mL) were measured for desferrioxamine, and 15.7 micro mol/L (9.6 micro g/mL) for ferrioxamine, 1 hour after an intramuscular injection of 10 mg/kg desferrioxamine. These patients eliminated desferrioxamine and ferrioxamine with half-lives of 5.6 and 4.6 hours respectively. Six hours after the injection 17% of the dose was excreted in the urine as desferrioxamine and 12% as ferrioxamine.

In patients dialysed for renal failure who received 40 mg/kg desferrioxamine infused i.v. within 1 hour, the plasma concentration at the end of the infusion was 152 micro mol/L (85.2 micro g/mL) when the infusion was given between dialysis sessions. Plasma concentrations of desferrioxamine were between 13% and 27% lower when the infusion was administered during dialysis. Concentrations of ferrioxamine were in all cases approximately 7.0 micro mol/L (4.3 micro g/mL) with concomitant aluminoxamine levels of 2-3 micro mol/litre (1.2-1.8 micro g/mL). After the infusion was discontinued, the plasma concentrations of desferrioxamine decreased rapidly with a half-life of 20 minutes. A smaller fraction of the dose was eliminated with a longer half-life of 14 hours. Plasma concentrations of aluminoxamine continued to increase for up to 48 hours post-infusion and reached values of approximately 7 micro mol/L (4 micro g/mL). Following dialysis the plasma concentration of aluminoxamine fell to 2.2 micro mol/L (1.3 micro g/mL), indicating that the aluminoxamine complex is dialysable.

In patients with thalassaemia continuous intravenous infusion of 50mg/kg/24h of desferrioxamine resulted in plasma steady state levels of desferrioxamine of 7.4 micro mol/L. Elimination of desferrioxamine from plasma was biphasic with a mean distribution half-life of 0.28 hours and an apparent terminal half-life of 3.0 hours. The total plasma clearance was 0.5 L/h/kg and the volume of distribution at steady state was estimated at 1.35 L/kg. Exposure to the main iron binding metabolite was around 54% of that of desferrioxamine in terms of AUC. The apparent monoexponential elimination half-life of the metabolite was 1.3 hours.

There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the summary.