Tens of thousands of transfusion-dependent (eg,
thalassemia) patients worldwide suffer from chronic
iron overload and its potentially fatal complications. The oral
iron chelator deferasirox has become commercially available in many countries since 2006. Although this alternative to parenteral
deferoxamine has been a major advance for patients with transfusional
hemosiderosis, a proportion of patients have suboptimal response to the maximum approved doses (30 mg/kg per day), and do not achieve negative
iron balance. We performed a prospective study of oral
deferasirox pharmacokinetics (PK), comparing 10 transfused patients with inadequate
deferasirox response (rising
ferritin trend or rising liver
iron on
deferasirox doses > 30 mg/kg per day) with control transfusion-dependent patients (n = 5) with adequate response. Subjects were admitted for 4 assessments:
deferoxamine infusion and urinary
iron measurement to assess readily chelatable
iron; quantitative hepatobiliary scintigraphy to assess hepatic uptake and excretion of chelate; a 24-hour
deferasirox PK study following a single 35-mg/kg dose of oral
deferasirox; and pharmacogenomic analysis. Patients with inadequate response to
deferasirox had significantly lower systemic drug exposure compared with control patients (P < .00001). Cmax, volume of distribution/bioavailability (Vd/F), and elimination half-life (t(1/2)) were not different between the groups, suggesting bioavailability as the likely discriminant. Effective dosing regimens for inadequately responding patients to
deferasirox must be determined. This trial has been registered at http://www.clinicaltrials.gov under identifier NCT00749515.