Safety, tolerability, and pharmacokinetics of ICL670, a new orally active iron-chelating agent in patients with transfusion-dependent iron overload due to beta-thalassemia.
ICL670 is an orally active representative of a new class of tridentate iron chelator developed for the treatment of blood transfusion-dependent iron overload in chronic anemias. In this randomized, double-blind study, patients with transfusion-dependent beta-thalassemia received single oral doses of ICL670 ranging from 2.5 to 80 mg/kg to investigate its safety, tolerability, and pharmacokinetics and to obtain preliminary information on pharmacodynamic effects. ICL670 was well tolerated, and no safety problems occurred up to 80 mg/kg. A plasma half-life of 11 to 19 hours was found for ICL670, supporting once-daily oral administration. AUC0-24 h and Cmax of ICL670 increased nearly proportionally with the dose. The urinary excretion of ICL670 and its iron complex was less than 0.1% of the dose, and this was in accordance with the expected predominant iron fecal excretion induced by ICL670 (based on preclinical experiments). Notwithstanding, a positive trend toward increased amounts of urinary excreted iron was observed when the AUC0-24 h of ICL670 and the iron complex exceeded specific threshold values at the 40- and 80-mg/kg dose levels.
Galanello
Renzo
R
Ospedale Regionale Microcitemie, Dipartimento di Scienze Biomediche e Biotecnologie, Università di Cagliari, Italy.
Piga
Antonio
A
Alberti
Daniele
D
Rouan
Marie-Claude
MC
Bigler
Hilde
H
Séchaud
Romain
R
D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D001565:Benzoates / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D000077588:Deferasirox; D004311:Double-Blind Method; D006207:Half-Life; D006801:Humans; D007501:Iron / Q000652:urine; D007502:Iron Chelating Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D012449:Safety; D014230:Triazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D017086:beta-Thalassemia / Q000188:drug therapy / Q000378:metabolism
D001565:Benzoates; D007502:Iron Chelating Agents; D014230:Triazoles; D007501:Iron; D000077588:Deferasirox