title: 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.
authors.affiliation: Hematology/Oncology, Children's Hospital Boston, Boston, MA 02115, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Chirnomas
authors.forename: Amber Lynn
authors.initials: AL
authors.lastname: Smith
authors.forename: Jennifer
authors.initials: J
authors.lastname: Braunstein
authors.forename: Yaron
authors.initials: Y
authors.lastname: Finkelstein
authors.forename: Luis
authors.initials: L
authors.lastname: Pereira
authors.forename: Anke K
authors.initials: AK
authors.lastname: Bergmann
authors.forename: Frederick D
authors.initials: FD
authors.lastname: Grant
authors.forename: Carole
authors.initials: C
authors.lastname: Paley
authors.forename: Michael
authors.initials: M
authors.lastname: Shannon
authors.forename: Ellis J
authors.initials: EJ
authors.lastname: Neufeld
mesh_terms: D000293:Adolescent; D000328:Adult; D000740:Anemia / Q000628:therapy; D001565:Benzoates / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001682:Biological Availability; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D000077588:Deferasirox; D005260:Female; D006801:Humans; D007502:Iron Chelating Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019190:Iron Overload / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D010597:Pharmacogenetics; D011446:Prospective Studies; D065227:Transfusion Reaction; D014230:Triazoles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D001565:Benzoates; D007502:Iron Chelating Agents; D014230:Triazoles; D000077588:Deferasirox