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Safety, Tolerability, and Pharmacokinetics of ICL670, a New Orally Active Iron-Chelating Agent in Patients with Transfusion-Dependent Iron Overload Due to ß-Thalassemia

From the Ospedale Regionale Microcitemie, Dipartimento di Scienze Biomediche e Biotecnologie, Università di Cagliari, Italy; Ospedale Regina Margherita, Dipartimento di Scienze Pediatriche, Centro Microcitemie, Torino, Italy; and Novartis Pharma AG, Origgio (Italy), Rueil-Malmaison (France), and Basel (Switzerland).

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 ß-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. AUC_0-24h and C_max 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 AUC_{0-24 h} of ICL670 and the iron complex exceeded specific threshold values at the 40- and 80-mg/kg dose levels.

Key Words: ICL670 • oral chelation • iron overload • pharmacokinetics • safety

Address for reprints: Dr. Romain Séchaud, Novartis Pharma AG, Exploratory Clinical Development, WSJ-27.3.086, CH-4002 Basel, Switzerland.

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