Pharmacokinetic and Toxicological Results of a 28-Day Multiple Dose Study of Starch-Conjugated Deferoxamine (S-DFO, 40SD02) in Iron-Loaded Dogs.

Starch-conjugated deferoxamine (S-DFO) is a long-acting, polymeric iron chelator designed to achieve iron balance in patients requiring frequent transfusions. Results from an ascending single dose study in 16 patients with beta-thalassemia showed that S-DFO is capable of achieving up to 7 days of iron balance (

1. to seek evidence of cardiovascular side-effects;

2. to find evidence of drug accumulation in plasma and other tissues; and

3. to determine the No Observable Adverse Effect Level (NOAEL) following biweekly intravenous infusion for 4 weeks.

Iron loading was achieved by multiple biweekly infusions of iron-dextran so as to give a cumulative dose of 500 mg of iron/kg body weight. Equilibration of iron was then allowed to proceed for 10 weeks before initiation of treatment. The study included four groups of 10 iron-loaded animals (5M/5F):

1. saline controls;

2. 210 and

3. 420 mg/kg of deferoxamine (DFO) equivalents as S-DFO;

4. 105 mg/kg of non-conjugated DFO;

and two groups of 10 normoferremic animals (5M/5F):

1. saline controls; and

2. 210 mg/kg of DFO equivalents as S-DFO.

All animals received 8 doses of either S-DFO, DFO or saline over 28 days. Six animals in each group (3M/3F) were euthanized on Day 29 for histological examination, the remaining 4 animals in each group on Day 43. Safety parameters for cardiovascular pharmacology, hematology and clinical chemistry showed no changes attributable to S-DFO treatment. The polymeric chelator is cleaved/metabolized by serum amylase(s). While trough concentrations of S-DFO fragments prior to the final drug infusion on Day 25 showed some accumulation, there was no evidence of resulting pathological changes. Thus, the NOAEL is at least 420 mg/kg of DFO equivalents. The hepatic iron content of the iron-loaded animals was approximately 20 times greater than that of the normoferremic controls. Treatment with 420 mg/kg of DFO equivalents led to a 13% reduction in the liver iron content. Neither iron loading nor treatment with S-DFO had a significant effect upon the cardiac iron status. The lack of toxicity in normoferremic animals suggests that S-DFO may have applications in clinical situations where increased iron stores are not characteristic of the disease. Furthermore, the ability to safely infuse up to 420 mg/kg of DFO equivalents without concern for hypotension indicates that S-DFO may also be well suited for treatment of acute iron poisoning. Finally, these results support initiation of multidose studies of S-DFO in patients with thalassemia and other iron overload disorders.

Supported by NIDDK Contract Number N01-DK-32624.