Plasma LPI in β-Thalassemia Patients before and after Treatment with Deferasirox (Exjade®, ICL670).
Authors: Daar S. , Taher A. , Pathare A. , Krahn U. , Gathmann I. , Nick H. , Hadler D. 
Published: April 2020

Background: Non-transferrin bound iron (NTBI) remains poorly defined and comprises both non-protein and protein-bound forms of iron. The non-protein ligands appear to correspond to low-molecular-weight organic compounds such as citrate. However, the majority of the NTBI component in plasma is bound to albumin. In patients with thalassemia, the accumulation of plasma NTBI correlates with the appearance of oxidation products, indicating increased oxidative stress in the presence of NTBI. Recently, a new methodology to determine the capacity of serum iron to form reactive oxidant species has been introduced (Esposito et al. 2003). One subcomponent of NTBI, the so-called labile plasma iron (LPI), is an iron-chelatable component of plasma that engages in redox cycling. LPI is a potential source of circulating iron responsible for tissue overload and consequent tissue damage, eg in the heart. Oxidant-sensitive fluorescent probes allow measurement of LPI via the radical forming capacity of plasma samples.

Methods: As part of the Novartis trial ESCALATOR that investigates efficacy and safety of deferasirox (DSX), a novel oral iron chelator, in β-thalassemia patients from the Middle East, a subset of patients treated with 20 mg/kg/day DSX were evaluated for LPI. The goals of this study were a) to quantify LPI in plasma of DSX-naive patients and contrast these values with LPI levels measured 2 hours after DSX administration; b) to compare LPI levels obtained pre and post first administration of DSX with pre and post administration values obtained after repeat dosing of DSX at 4, 16, 28, 40 and 52 weeks after start of the study. This abstract summarizes the preliminary data available for 14 patients with LPI measurement at baseline and after 4 weeks.

Results: A statistically significant reduction in post administration LPI levels compared to pre administration LPI levels were seen at both assessments.

First administration (n=14) Repeat administration (n=14) LPI, μmol/L Pre Post Pre Post Mean ± SD 1.03 ± 0.80 0.14 ± 0.16 0.44 ± 0.58 0.09 ± 0.20 Median 0.82 0.07 0.25 0 25–75th percentiles 0.44–1.67 0–0.27 0.09–0.33 0–0.06 Minimum-maximum 0–2.65 0–0.5 0–1.75 0–0.75 Pre vs post admin P &lt;0.001 P =0.006 First vs repeat pre P =0.003

At first administration of DSX pre-dosing LPI levels averaged 1.03 ± 0.80 μmol/L. 2 hours after first administration of DSX, LPI levels dropped significantly to an average of 0.14 ± 0.16 μmol/L (P&lt;0.001, paired t-test). After repeat dosing of 20 mg/kg DSX for 4 weeks, pre-administration levels of LPI can be regarded as the LPI present at trough plasma concentrations of DSX. These LPI levels were significantly lower than initial LPI before first dosing and were close to normal LPI levels (0–0.4 μmol/L). This indicates that once-daily DSX potentially protects for 24 hours (average 0.44 at repeat dosing vs 1.03 μmol/L before first dosing, P=0.003 paired t-test). After 4 weeks, the drop to even lower post administration LPI levels may reflect the higher steady state concentrations of DSX after repeat dosing.

Conclusion: Based on this initial data, DSX given at single daily doses of 20 mg/kg resulted in significant reduction of LPI for 24 hours, indicating that once-daily administration potentially protects organs, including the heart and liver, from iron loading and consequent cellular and tissue damage.