Deferasirox pharmacokinetics in patients with adequate versus inadequate response

Abstract

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.

Figures

Figure 1

Pharmacokinetic assessments. (A) Mean systemic exposure levels (DSX-AUC) of each group over the 24-hour time course after administration. Error bars represent standard error. (Adequate responders [●]; inadequate responders [▵].) (B) Free DSX concentrations in individual study participants over the 24-hour time course after administration. The actual average dose per kilogram was 34.7 plus or minus 1.12 mg (SD). (Adequate responders [●]; inadequate responders [▵].). One inadequate responder has documented outpatient noncompliance but good exposure in observed therapy setting. (2): The youngest inadequate responder has very rapid clearance and low exposure. Total DSX (free DSX +Fe [ICL670]2) yielded similar results (not shown). (C) Box and whisker plots of exposure (area under the curve) of free DSX levels in responders versus inadequate responders (P < .001). Box represents median interquartile range and whiskers are minimum to maximum range. Generated with the Mann-Whitney test.