title: Comparison of deferoxamine pharmacokinetics between asymptomatic thalassemic children and those exhibiting severe neurotoxicity.
abstract: The use of deferoxamine for iron chelation in transfusion-dependent thalassemia major is limited by serious neurotoxicity (hearing and vision loss). We assessed whether interpatient variability in handling deferoxamine and resultant accumulation of the drug may account for the neurotoxicity. We studied steady-state deferoxamine pharmacokinetics during intravenous infusion in two groups of patients--one group exhibited severe manifestations of auditory and visual loss and one group was asymptomatic. The groups were matched for age, sex distribution, weight, treatment period, ferritin levels, and hemoglobin levels. Similarly, doses of deferoxamine at the time of the study were not different. Clearance rates were not different between the symptomatic and asymptomatic patients (39.83 +/- 4.54 versus 30.66 +/- 4.39 ml/min.kg). However, patients who exhibited toxicity received significantly higher daily doses of subcutaneous deferoxamine at the time of diagnosis of neurotoxicity (9.03 +/- 0.96 and 5.58 +/- 0.61 mg/kg.hr, respectively; p less than 0.005). These data suggest that deferoxamine induced neurotoxicity is dose-dependent and cannot be attributed to accumulation of the drug caused by slower clearance rates.
authors.affiliation: Division of Clinical Pharmacology, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Y
authors.initials: Y
authors.lastname: Bentur
authors.forename: G
authors.initials: G
authors.lastname: Koren
authors.forename: A
authors.initials: A
authors.lastname: Tesoro
authors.forename: H
authors.initials: H
authors.lastname: Carley
authors.forename: N
authors.initials: N
authors.lastname: Olivieri
authors.forename: M H
authors.initials: MH
authors.lastname: Freedman
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D003676:Deferoxamine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007263:Infusions, Parenteral; D008297:Male; D008657:Metabolic Clearance Rate; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000378:metabolism; D013789:Thalassemia / Q000188:drug therapy / Q000378:metabolism*
chemical_list: D003676:Deferoxamine