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IN VITRO BLOOD DISTRIBUTION AND PLASMA PROTEIN BINDING OF THE IRON CHELATOR DEFERASIROX (ICL670) AND ITS IRON COMPLEX FE-[ICL670]₂ FOR RAT, MARMOSET, RABBIT, MOUSE, DOG, AND HUMAN

Novartis Pharma AG, Exploratory Development/Drug Metabolism and Pharmacokinetics, Basel, Switzerland

Deferasirox (Exjade, ICL670) is an orally active iron chelator. Two molecules of deferasirox can form a complex with ferric iron (Fe-[ICL670]₂) that can be excreted, reducing body iron overload. The blood binding parameters across species and the interaction with human serum albumin were analyzed for deferasirox and its iron complex. Both molecules were very highly bound to plasma proteins in all the tested species with unbound fractions in plasma in the range of 0.4 to 1.8% and 0.2 to 1.2% for deferasirox and Fe-[ICL670]₂, respectively; binding of the iron complex was either similar or higher in all the species. The high plasma protein binding was in line with a distribution mainly into the plasma fraction of blood; the fraction in plasma was around 100% for Fe-[ICL670]₂ in all the species and 65 to 95% for deferasirox depending on the species. Investigations with isolated proteins pointed to serum albumin as the principal binding protein for deferasirox and its iron complex in human plasma. Competition binding experiments indicated that deferasirox at high concentrations displaced markers from the two main drug binding sites of human albumin, whereas Fe-[ICL670]₂ displaced only warfarin. In the context of the pharmacokinetic properties of deferasirox and Fe-[ICL670]₂, the data indicate the importance of plasma protein binding for their disposition and support a comparison of the pharmacokinetics of deferasirox and its iron complex across species. The low likelihood of clinically relevant drug displacement by deferasirox in plasma is discussed.

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