Superparamagnetic iron oxide: pharmacokinetics and toxicity

TLDR

The study evaluated the pharmacokinetics and toxicity of the superparamagnetic iron oxide AMI‑25 using 59Fe radiotracer, relaxation time measurements, anemia reversal tests, histology, and laboratory parameters. In rats, 82.6 % of AMI‑25 was sequestered in liver and 6.2 % in spleen within 1 h, with peak liver concentrations at 2 h and spleen at 4 h, slow clearance (t½ ≈ 3 days liver, 4 days spleen), incorporation into erythrocyte hemoglobin, and a T2 effect lasting 24–48 h; IV dosing of 30 mg Fe/kg corrected iron‑deficiency anemia with bioavailability comparable to commercial IV iron, and no acute or subacute toxicity was observed even at 150× the proposed imaging dose, indicating AMI‑25 is a fully biocompatible MR contrast agent.

Abstract

The pharmacokinetics (distribution, metabolism, bioavailability, excretion) and toxicity (acute and subacute toxicity, mutagenicity) of a superparamagnetic iron oxide preparation (AMI-25), currently used in clinical trials, were evaluated by 59Fe radiotracer studies, measurements of relaxation times, the ability to reverse iron deficiency anemia, histologic examination, and laboratory parameters. One hour after administration of AMI-25 to rats (18 mumol Fe/kg; 1 mg Fe/kg), 82.6 +/- 0.3% of the administered dose was sequestered in the liver and 6.2 +/- 7.6% in the spleen. Peak concentrations of 59Fe were found in liver after 2 hr and in the spleen after 4 hr. 59Fe slowly cleared from liver (half-life, 3 days) and spleen (half-life, 4 days) and was incorporated into hemoglobin of erythrocytes in a time-dependent fashion. The half-time of the T2 effect on liver and spleen (24-48 hr) was shorter than the 59Fe clearance, indicating metabolism of AMI-25 into other forms of iron. IV administration of AMI-25 (30 mg Fe/kg) corrected iron-deficiency anemia and showed bioavailability similar to that of commercially available IV iron preparations within 7 days. No acute or subacute toxic effects were detected by histologic or serologic studies in rats or beagle dogs who received a total of 3000 mumol Fe/kg, 150 times the dose proposed for MR imaging of the liver. Our results indicate that AMI-25 is a fully biocompatible potential contrast agent for MR.