Pharmacokinetics of aluminoxamine and ferrioxamine and dose finding of desferrioxamine in haemodialysis patients

Abstract

We investigated the pharmacokinetics of desferrioxamine and its chelated compounds aluminoxamine and ferrioxamine in normal volunteers and haemodialysis patients with and without iron overload. Desferrioxamine was administered in a single dose of 30 mg per kg body-weight was a 30-min infusion to five healthy volunteers and to 20 haemodialysis patients (five patients without haemosiderosis and 15 patients with haemosiderosis). The interdialytic half-life of ferrioxamine was 2.2 h in normal volunteers, 13.3 h in dialysis patients without haemosiderosis, and 24.6 h in patients with haemosiderosis. There was no interdialytic elimination of aluminoxamine. In a second study, seven dialysis patients received 5, 10, and 20 mg per kg body-weight desferrioxamine in a random order with a time interval of 2 weeks. The peak serum concentrations after these doses were 4.1 +/- 2.9, 6.4 +/- 2.9, and 10.7 +/- 7.1 mumol/l for ferrioxamine and 2.8 +/- 1.5, 3.1 +/- 1.5, and 4.2 +/- 1.7 mumol/l for aluminoxamine. Thus, a 4-fold increase in desferrioxamine dosage resulted in a 2.7-fold increase in peak ferrioxamine levels and in only a 1.5-fold increase in peak aluminoxamine levels. We conclude that dialysis patients, especially those with haemosiderosis, are exposed to persistently elevated ferrioxamine levels. Weekly doses of 5-10 mg/kg of desferrioxamine would be sufficient for aluminium chelation therapy.

Mucormycosis during deferoxamine therapy is a siderophore-mediated infection. In vitro and in vivo animal studies.

“…This is in keeping with the central role played by Fe.DFO in the pathogenesis of this infection when developing during DFO therapy. Indeed, pharmacokinetic changes in uremia lead to a sixfold prolongation ofthe elimination halftime and a 4.9-fold increase in the area under the concentration-time curve for Fe.DFO in dialysis patients, when compared with subjects with normal renal function, after one single DFO administration (38). 44 In vivo pretreatment ofmice with aluminum salts has no effect upon the susceptibility to Rhizopus infection (39), whereas pretreatment with iron salts aggravates the infection (3,29).…”

Estimation of Statistical Moments for Desferrioxamine and Its Iron and Aluminium Chelates: Contribution to Optimisation of Therapy in Uremic Patients

“…The studies regarding the kinetics of DFO and its che lates in uremic patients are few and empirical [7,14], Only in 1992 was a paper published with well-formalized classical pharmacokinetics [9]. Since, to our knowledge, no other study was performed, we considered worthwhile to present our data, although this was not the main pur pose of the investigation.…”

“…The kinetic studies have prompted an effort in opti mizing DFO therapy, and this has become the most important goal in the last years [9,10]. The effective dose has been reduced, but the most suitable time of adminis tration of the drug with regard to the dialysis session is not clearly defined.…”

The Role of Chelation in the Treatment of Other Metal Poisonings

“…Third, the potential toxicities of the unbound DFO chelator, as well as the toxicities of both chelates-AlO and ferrioxamine (FO)-must be anticipated. AlO and FO following DFO administration may persist for long periods, especially in kidney disease [32,33].…”