The Safety and Pharmacokinetics of Deferitrin, a Novel Orally Available Iron Chelator.
Authors: Donovan Joanne M. , Yardumian Anne , Gunawardena Kulasiri A. , Plone Melissa A. , Wonke Beatrix 
Published: October 2019

Abstract
Background: Deferitrin (GT56-252) is an orally active, tridentate, iron chelator under development to treat chronic iron overload conditions resulting from transfusion therapy. The compound is derived from desferrithiocin specifically modified to minimize toxicity associated with the parent compound (Bergeron et al., 1999). Deferitrin effects iron excretion with an efficiency of 13–18% when administered orally to Cebus apella monkeys, a species whose iron metabolism closely resembles that of humans. Iron excretion is predominantly by the fecal route (80–90%).
Methods: This Phase 1 trial was an open-label, parallel-design, two-dose study. The study consisted of a screening period, a confinement period during which a single dose of deferitrin was administered on two consecutive days with pharmacokinetic measurements, and a follow-up visit. Twenty-six patients, divided in five panels, received at least one dose of deferitrin over two days, either fasted or fed, at five dose levels from 3 to 15 mg/kg. Deferitrin was administered as liquid (3 and 4.5 mg/kg), or as 50 or 250 mg capsules (4.5, 8, 11, and 15 mg/kg). Blood samples were taken at intervals up to 24 hours to characterize the pharmacokinetics of deferitrin, and 24-hour urine collections were conducted to measure deferitrin excretion. Safety laboratories included chemistry and hematology panels, coagulation parameters, urinalysis, and urine beta-2-microglobulin. Additional safety evaluations included physical examinations and electrocardiogrammes (ECG).
Results: Deferitrin was well tolerated. There were no serious adverse events while patients were confined; however, one patient with pre-existing diabetes who received 4.5 mg/kg was hospitalized after an episode of hypoglycemic coma three days after the second dose. This had been a recurring phenomenon in this patient, and was determined by the investigator to be unrelated to administration of deferitrin. There were no clinically significant changes in safety laboratories, including chemistry, hematology, and coagulation studies, in urinalyses or urinary beta-2-microglobulin levels. ECGs performed before and after dosing were unremarkable. The AUC for the fed and fasted states were similar, both for the liquid and capsule, suggesting that bioavailability is not impaired by food. From 13 to 48% of the drug was present in serum as the 2:1 deferitrin: iron complex. The T½ (approximately 2 to 4 hours) was similar for all doses. Preliminary measurement of deferitrin levels in the urine showed recovery of approximately 75% at all doses. Approximately 2% of the deferitrin in the urine was complexed to iron.
Conclusion: In this initial clinical study, deferitrin was safe, well-tolerated, and well-absorbed either with food and fasting in beta-thalassemia patients. Renal excretion of deferitrin uncomplexed with iron was similar to that seen in preclinical studies, which predict iron excretion to be via the fecal route. Further studies are ongoing to define the effect of deferitrin on iron balance.